CN103145616A - Novel nitrogen-containing heteroaryl compounds and methods of use thereof - Google Patents

Novel nitrogen-containing heteroaryl compounds and methods of use thereof Download PDF

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CN103145616A
CN103145616A CN201210387408XA CN201210387408A CN103145616A CN 103145616 A CN103145616 A CN 103145616A CN 201210387408X A CN201210387408X A CN 201210387408XA CN 201210387408 A CN201210387408 A CN 201210387408A CN 103145616 A CN103145616 A CN 103145616A
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hydroxyl
isoquinoline
amino
carbonyl
substituted
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CN103145616B (en
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迈克尔·P·阿兰德
李·A·弗利平
福尔克马·京茨勒–普卡尔
何文彬
埃里克·D·图尔托
杜晓辉
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Fibrogen Inc
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    • C07D217/24—Oxygen atoms

Abstract

The present invention relates to compounds suitable for use in mediating hypoxia inducible factor and for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo.

Description

Nitrogen-containing heteroaryl compounds and the purposes in increasing endogenous erythropoietin thereof
The application is that application number is 200480015559.6 (PCT/US2004/017773), the dividing an application of the Chinese invention patent application that the applying date is on June 4th, 2004 " nitrogen-containing heteroaryl compounds and the purposes in increasing endogenous erythropoietin thereof ".
The cross reference of related application
The application's case is advocated the U.S. Provisional Patent Application case the 60/476th of application on June 6th, 2003, No. 811; The 60/476th of application on June 6th, 2003, No. 420; The 60/476th of application on June 6th, 2003, No. 633; With the 60/476th of application on June 6th, 2003, No. 519 rights under United States Code the 35th volume the 119th (e) bar; The full text of all described application cases is incorporated herein by reference.
Technical field
The method and the compound that the present invention relates to regulate the stability of hypoxia inducible factor (HIF) alpha subunit and increase endogenous erythropoietin in external and body.
Background technology
An early response of histanoxia is inducing of hypoxia inducible factor (HIF), hypoxia inducible factor is the agent of a kind of alkaline helix-loop-helix (bHLH) PAS (Per/Arnt/Sim) transcriptional activation, the change of the genetic expression that its regulation and control change with the cell oxygen concn.HIF is a kind of heterodimer that an oxygen is regulated alpha subunit (HIF α) and a constructive expression β subunit (HIF β) that contains, and is also referred to as aryl hydrocarbon receptor importin (ARNT).In oxygenate (normal oxygen) cell, the HIF alpha subunit is degraded rapidly by the mechanism that relates to retinal angiomatous (von Hippel-Lindau tumor) arrestin (pVHL) E3 ligase enzyme mixture ubiquitin.Under anoxia condition, HIF α does not degrade, and the expression of some genes is accumulated and activated to a kind of active HIF α/β mixture in nucleus, comprise glycolytic ferment, glucose transporter (GLUT)-1, erythropoietin (EPO) and vascular endothelial growth factor (VEGF).(people such as Jiang, (1996) " journal of biological chemistry " (J.Biol.Chem.), 271: 17771-17778; The people such as Iliopoulus, (1996) " PNAS " (Proc.Natl.Acad.Sci.USA), 93: 10595-10599; The people such as Maxwell, (1999) " nature " (Nature), 399: 271-275; The people such as Suiter, (2000) " PNAS ", 97: 4748-4753; The people such as Cockman, " journal of biological chemistry ", 275: 25733-25741; With people such as Tanimoto, (2000) " European molecular biology journal " (EMBO.J.) 19: 4298-4309).
In most cells, the content of HIF α albumen improves with anoxic, and, when animal suffers from anaemia or anoxic, induces HIF α in body.In several hours after anoxic starts, the content of HIF α raises and is continuing to get back to baseline under anoxia condition.HIF has related in numerous cell evolutions, comprises cell proliferation, vasculogenesis and cell cycle arrest.HIF α also with Acute myocardial ischemia and early stage infraction, pulmonary hypertension and inflammation-related.Although HIF α, with tumor growth and shift relevantly, has a little sign to mean that HIF is directly involved in tumour and occurs.The anoxic pre-treatment has shown can protect cardiac muscle and brain not to be subject to anoxic-ischemic damage, and wherein target organ suffers from the short-term anoxic.The stability of HIF α and local asphyxia are closely related and pass through pretreatment induction.(Wang and Semenza, (1993) " PNAS ", 90:4304-4308; The people such as Stroka, (2001) " U.S. bioorganism medical association magazine " (FASEB.J.), 15: 2445-2453; The people such as Semenza, (1997) " international kidney magazine " (Kidney Int.), 51: 553-555; The people such as Carmeliet, (1998) " nature " 394: 485-490; The people such as Zhong, (1999) " cancer research magazine " (Cancer Res.), 59: 5830-5835; The people such as Lee, (2000) " New England Journal of Medicine " (N.Engl.J.Med.), 343: 148-149; The people such as Sharp, (2000) " cerebral blood flow and metabolism magazine " (J.Cereb.Blood Flow Metab.), 20:1011-1032; The people such as Semenza, (2000) " experimental medicine and biology progress " (Adv.Exp.Med.Biol.), 475: 123-130; The people such as Thornton (2000) " journal of biological chemistry " (Biochem.J.), 350: 307-312; Deindl and Schaper, (1998) " molecule and cellular biochemistry " (Mol.Cell.Biochem.), 186: 43-51; The people such as Bergeron, (2000) " neuroscience annual report " (Ann.Neurol.), 48: 285-296).
Some investigators are studied the interaction mechanism between HIF α and pVHL.Think that at first the interior oxygen dependence degraded territory (ODD) from residue 401 to 603 of HIF-1 α is enough to give chimeric protein structure oxygen dependence unstable.It is found that the degraded of pVHL dependency need to be from the territory of containing ODD albumen of residue 526 to 652.On the other hand, in zone in being stored in HIF alpha homologues (in HIF-1 α, residue 556 to 574), P564YI sports aspartic acid or K532 and sports arginine and make under normal oxygen condition, and the protein stabilized and opposing of whole body HIF α is by the degraded of pVHL mediation.(people such as Huang, (1998) " PNAS ", 95: 7987-7992; With people such as Tanimoto, (2000) " European molecular biology journal ", 19: 4298-4309).
The HIF alpha content increases by many simulation anoxic factors, comprises iron chelating agent, for example desferrioxamine (DFO) and divalent metal, for example CoCl 2.The HIF alpha content is to utilize the mechanism that relates to active oxygen to increase by Angiotensin II, zymoplasm and Thr6 PDGF BB under normal oxygen condition.Report also proposes, and HIF α regulates by phosphorylation, the path of the protein kinase that it activates via the phosphatidylinositols 3'-kinases (PI3K) that relates to the nitrogen protoxide activation, pHGF or mitogen.Glycogen synthase kinase Direct Phosphorylation HIF α ODD territory as the downstream target thing of PI3K.(people such as Richard, (2000) " journal of biological chemistry " (J.Biol.Chem.), 275: 26765-26771; The people such as Sandau, (2000) " biological chemistry and biophysical research communication " (Biochem.Biophys.Res.Commun.), 278: 263-267; The people such as Tacchini, (2001) " the carcinogenic magazine of molecule " (Carcinogenesis), 22:1363-1371; With people such as Sodhi, (2001) " biological chemistry and biophysical research communication ", 287: 292-300).
Erythropoietin (EPO) is a kind of hormone naturally existed produced with HIF α, and it stimulates delivery oxygen to run through the generation of the red corpuscle (red blood corpuscle) of whole body.EPO is usually by renal secretion, and endogenous EPO increases under the condition of oxygen minimizing (anoxic).The all types anaemia is characterised in that the ability of blood delivery oxygen reduces, and thereby with similar sign and symptom, comprise skin and mucosal pallor, weakness, dizziness, fatiguability and drowsiness, cause the decline of quality of life.Experimenter with serious anaemia situation shows and is difficult to breathe and heart malformations.Anaemia is usually relevant with the leiphemia patient's condition in red corpuscle or in oxyphorase.
The common reason of anaemia comprises iron, vitamins B 12and folic acid deficiency.Anaemia also can be concurrent with chronic disease, and for example inflammatory conditions, comprise illness with the inhibition of secondary marrow inflammatory etc.Anaemia can cause by losing blood, for example, due to accident, operation or by the drug-induced gastrointestinal hemorrhage of for example acetylsalicylic acid and Ibuprofen BP/EP.Excessively lose blood and also be found in the women of Massive Bleeding in menstrual period, and in the crowd of containing stomach ulcer, duodenal ulcer, hemorrhoid or cancer of the stomach or large bowel cancer etc.
Multiple condition can cause erythrocytic destruction (haemolysis), thereby causes anaemia.For example, can cause haemolysis to the anaphylactic type reaction of bacteriotoxin and number of chemical reagent, for example sulfamido and benzene.Hemolytic anemia is often caused by chemical poisoning, parasite, infection or sicklemia.In addition, there is abnormal case, health himself the erythrocytic antibody that creates antagonism wherein, thus cause haemolysis.Any bone marrow disease or damage can cause anaemia, because this tissue is red blood corpuscle, generate, i.e. the synthetic place of red blood corpuscle.Radiation, disease or number of chemical reagent also can cause that marrow destroys, and produces aplastic anemia.Experience chemotherapeutic cancer patients and often there is aplastic anemia.Anaemia is also relevant with renal tubal dysfunction, the seriousness of anaemia and handicapped degree height correlation.Most of chronic renal failure patients of experience dialysis suffer from chronic anaemia.
Except producing in kidney, erythropoietin also produces in central nervous system (CNS) by stellate cell and neurone, and EPO and EPO acceptor are expressed on the kapillary at interface, brain periphery.In addition, the EPO of whole body dispensing passes through hemato encephalic barrier and reduces the neurocyte loss produced with brain and spinal cord local asphyxia, mechanical injury, epilepsy, excitotoxin and neural inflammation.(Sakanaka, (1998) " PNAS ", 95: 4635-4640; The people such as Celik, (2002) " PNAS ", 99: 2258-2263; The people such as Brines, (2000) " PNAS ", 97: 10526-10531; The people such as Calapai, (2000) " European pharmacology magazine " (Eur.J.Pharmacol.), 401: 349-356; With people such as Siren, (2001) " PNAS ", 98: 4044-404).
In the recent eighties, Amgen proposes a kind of genetic engineering EPO that is used for the treatment of the anaemia of patients with chronic renal failure.Also EPO is cast to experience radiation and/or chemotherapeutic cancer patients, to reduce its needs for blood transfusion.By the anaemia that EPO is used for the treatment of to HIV infects or Zidovodine (AZT) therapy is relevant.Although the market of EPO therapy is cumulative, this product expensive adversely affects following sale.In addition, the recombinant epo therapy needs intravenously EPO dispensing 1 to 3 time weekly, and nearly 12 weeks, the treatment plan restriction was offerd medicine voluntarily and the patient is brought inconvenience.On the other hand, owing to extensively reaching the glycosylation changed, in any ARANESP, no longer produce, old friend's class serum EPO shows big or small ununiformity.
The anoxic patient's condition of inducing HIF α to produce is that a kind of oxygen reduces state, and it can occur when lung damage or Oligemia.Local asphyxia (Oligemia) can cause by artery or vein obstruction, and described obstruction is by clot (thrombus) or for example, by any external recycled material (embolus) or, by vascular disorder, atherosclerosis causes.Oligemia can start suddenly and the time length short (acute ischemic), or can slowly start but the time length long or (chronic local asphyxia) frequently occur again.Acute ischemic is normal and local, irreversible tissue necrosis (a kind of infarct) is relevant, yet chronic local asphyxia is often damaged relevant with transience oxygen-starved tissue.If, yet perfusion reduces prolongation or serious, chronic local asphyxia also can be relevant in infarct.Infraction generally betides spleen, kidney, lung, brain and the heart, produces illness, for example intestinal obstruction, lung infraction, ishemic stroke and myocardial infarction.
The pathological change of ischemic conditions is looked ischemic time length and seriousness, and the patient is survived length and determines.Downright bad also being found in first 24 hours of infraction, and acute inflammatory response occurs in the living tissue of contiguous infraction, and white corpuscle is to the necrotic tissue zone migration simultaneously.Experience several days subsequently, decompose gradually and remove the infraction inner cell by phagolysis, and replacing with reduces collagen production or neuroglia scar.
Hypoperfusion in organ or infraction often affect other organ.For example, the lung local asphyxia caused by pulmonary infarction not only affects lung, and for example makes, under the heart and the pressure of other organ (brain) in anoxic.Myocardial infarction can cause congestive heart failure and systemic hypertension, and it is usually directed to the coronary occlusion caused due to thrombosis, ductus arteriosus wall spasm or heart trouble toxinfection.If asystolia extends and continues hypoperfusion, secondary complication can occur, for example the global ischemia encephalopathy (HIE).The most general because atherosclerosis causes that the cerebral ischaemia that vascular occlusion causes can be by transient ischemic attack (TIA) to cerebral infarction or apoplexy on seriousness.Although the symptom of TIA is temporary transient and reversible, TIA trends towards recurrence and is then often apoplexy.
Arteriosclerosis obliterans comprises the coronary artery disease that can cause myocardial infarction, and can affect aorta abdominalis, the peripheral arterial disease of its Main Branches and leg artery.Peripheral arterial disease comprises Buerger's disease (Buerger's disease), Raynaud disease (Raynaud's disease) and acrocyanosis.Although peripheral arterial disease generally causes by atherosclerosis, other major cause comprises such as diabetes etc.The complication relevant with peripheral arterial disease comprises serious shank spasm, stenocardia, irregular pulse, heart failure, heart trouble, apoplexy and renal failure.
Local asphyxia and anoxic illness are morbidity and main causes of death.Cardiovascular diseases causes at least one 15,000,000 dead every year and is the reason that causes the whole world 30% death.In multiple cardiovascular diseases, ischemic heart disease and cerebro-vascular diseases cause approximately 17% death.Annual report has the case of 1,300,000 non-lethal Acute Myocardial Infarctions, forms the sickness rate of 300 people in about every 100,000 people.On the other hand, estimating has 5,000,000 Americans to suffer from phlebothrombosis disease every year, and approximately 600,000 these cases cause pulmonary infarction.Approximately 1/3rd Pulmonary Embolism Patients is finally dead, makes pulmonary infarction become the 3rd of American's death common reason.
Current, the treatment of local asphyxia and anoxic illness concentrates on alleviating in the treatment with pathogenic illness of symptom.For example, the treatment of myocardial infarction comprises in order to control pain and alleviates pannonit and the anodyne that heart working is loaded.Use other medicines, comprise that digoxin (digoxin), diuretic(s), amrinone (amrinone), beta blocker, lipid lowering agent and angiotensin converting enzyme inhibitor stablize the patient's condition, but in these therapies, neither one can directly act on the tissue damage produced by local asphyxia and anoxic.
Produce and use the deficiency in recombinant epo owing to reaching in current treatment, so still need effectively to treat the compound of following disease: the erythropoietin related conditions, anaemia for example, comprise the anaemia relevant to diabetes, anaemia, ulcer, renal failure, cancer, infection, dialysis, operation and chemotherapy and relate to local asphyxia and the patient's condition of anoxic, for example arteriosclerosis obliterans, stenocardia, intestinal obstruction, lung infraction, cerebral ischaemia and myocardial infarction.Also need the compound of the tissue damage that effectively prevention is caused by local asphyxia, described local asphyxia is because for example lung's illness of atherosclerosis, diabetes and for example pulmonary infarction and similar conditions thereof occurs.In a word, need to regulate HIF and/or endogenous erythropoietin in technique, and can be used for treating method and compound relevant with prevention HIF and the EPO associated conditions, described illness comprises the patient's condition that relates to anaemia, local asphyxia and anoxic.
Summary of the invention
The present invention relates to regulate compounds and the method for hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO).
An aspect of the compounds of this invention provides the compound meaned by formula I:
Figure BDA00002247957200051
Wherein:
Q is 0 or 1;
P is 0 or 1;
R abe-COOH or-WR 8; Restricted condition is for working as R aduring for-COOH, p is 0 and works as R afor-WR 8the time p be 1;
The W choosing group that freely following each base forms: oxygen ,-S (O) n-and-NR 9-, wherein n is 0,1 or 2, R 9the choosing group that freely following each base forms: hydrogen, alkyl, be substituted alkyl, acyl group, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle and R 8the choosing group that freely following each base forms: hydrogen, alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, or as W be-NR 9-time, R 8and R 9nitrogen-atoms together with its combination can be connected to form heterocycle or be substituted heterocycle, and restricted condition is for as W being-S (O) n-and n be 1 or 2 o'clock, R 8be not hydrogen;
R 1the choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Amino; Be substituted amino; Aminoacyl; Aryl; Be substituted aryl; Halogen; Heteroaryl; Be substituted heteroaryl; Heterocycle; Be substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6the choosing group that freely following each base forms: alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, and R 7for hydrogen, alkyl or aryl, or as X be-NR 7-time, R 7and R 8nitrogen-atoms together with its combination can be connected to form heterocycle or be substituted heterocyclic radical;
R 2and R 3the independent choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Halogen; Hydroxyl; Cyano group;-S (O) n-N (R 6)-R 6, wherein n is 0,1 or 2;-NR 6c (O) NR 6r 6;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, each R 6the independent choosing group that freely following each base forms: hydrogen, alkyl, be substituted alkyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, restricted condition for as X being-SO-or-SO 2-time, R 6be not hydrogen, and R 7the choosing group that freely following each base forms: hydrogen, alkyl, aryl, or R 2, R 3together with side joint, carbon atom thereon forms aryl, the heteroaryl replaced through aryl or is substituted heteroaryl;
R 4and R 5the independent choosing group that freely following each base forms: hydrogen; Halogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6the choosing group that freely following each base forms: alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, and R 7for hydrogen, alkyl or aryl, or as X be-NR 7-time, R 7and R 8nitrogen-atoms together with its combination can be connected to form heterocycle or be substituted heterocyclic radical;
The group that R selects free hydrogen, deuterium and methyl to form;
R' selects free hydrogen, deuterium, alkyl and is substituted the group that alkyl forms; Perhaps, R and R' and side joint carbon thereon can be connected to form cycloalkyl, be substituted cycloalkyl, heterocycle or be substituted heterocyclic radical;
R " group or the R that select free hydrogen and alkyl to form " can be connected to form heterocycle or be substituted heterocyclic radical together with R' and side joint nitrogen thereon;
R ' " the choosing group that freely following each base forms: hydroxyl, alkoxyl group, be substituted alkoxyl group, acyloxy, cycloalkyloxy, be substituted cycloalkyloxy, aryloxy, be substituted aryloxy, heteroaryloxy, be substituted heteroaryloxy, aryl ,-S (O) n-R 10r wherein 10the choosing group that freely following each base forms: alkyl, be substituted alkyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl and be substituted heteroaryl, and n is 0,1 or 2;
And pharmaceutically acceptable salt, ester and prodrug;
Restricted condition is as R, R' and R, and " be hydrogen, q is 0, R afor-COOH (p is 0) or-WR 8(p is 1), W is oxygen and R 8during for hydrogen, following at least one situation occurs:
1) R 1for fluorine-based; Bromo; Iodo; Alkyl; Be substituted alkyl; Alkoxyl group; Aminoacyl; Be substituted alkoxyl group; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Heterocycle; Be substituted heterocycle; And-XR 6, wherein X is oxygen;-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6the choosing group that freely following each base forms: alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, and R 7for hydrogen, alkyl or aryl; Or
2) R 2for being substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Fluorine-based; Bromo; Iodo; Cyano group;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6the choosing group that freely following each base forms: alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 2when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; And
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise benzyl or through selecting freedom (C 1-C 5) alkyl and (C 1-C 5) benzyl that replaces of the substituting group of the group that forms of alkoxyl group or the Fluoroalkyloxy substituting group that does not comprise following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
3) R 3for being substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Bromo; Iodo;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6the choosing group that freely following each base forms: alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 3when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; And
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise benzyl or via being selected from (C 1-C 5) alkyl and (C 1-C 5) benzyl that replaces of the substituting group of the group that forms of alkoxyl group or the Fluoroalkyloxy substituting group that does not comprise following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
4) R 4for iodo; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6the choosing group that freely following each base forms: alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 4when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; And
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise the Fluoroalkyloxy substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
5) R 5for iodo; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6the choosing group that freely following each base forms: alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 5when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; And
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise the Fluoroalkyloxy substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1);
And further there is following restricted condition:
Work as R 1, R 3, R 4and R 5during for hydrogen, R 2it is not bromo.
In an alternate embodiment, the compound of formula I is meaned by formula IA:
Figure BDA00002247957200081
R wherein 1, R 2, R 3, R 4, R 5, R, R', R ", R ' " and q as above define; And pharmaceutically acceptable salt, ester, prodrug.
In another alternate embodiment, the compound of formula I is meaned by formula IB:
Figure BDA00002247957200091
R wherein 1, R 2, R 3, R 4, R 5, R ", R ' ", WR 8with q, as above define; And pharmaceutically acceptable salt, ester, prodrug.
In another alternate embodiment, the present invention is directed to the compound meaned by formula IC:
Figure BDA00002247957200092
R wherein 1, R 2, R 3, R 4, R 5, R, R', R ", R ' ", WR 8with q, as above define; And
Its pharmaceutically acceptable salt, ester, prodrug.
In another alternate embodiment, the present invention is directed to the compound meaned by formula ID:
Figure BDA00002247957200093
R wherein 1, R 2, R 3, R 4, R 5, R, R', R ", R ' " and q as above define; And pharmaceutically acceptable salt, ester, prodrug.
In other embodiments, the present invention is directed to the compound meaned by formula IIA, IIB, IIC and IID, wherein said formula is as hereinafter defined.
Preferred embodiment
In the compound of formula I, IA, IB, IC and ID, R 1the better choosing group that freely following each base forms: hydrogen, alkyl, be substituted alkyl, halogen, alkoxyl group, aryloxy, be substituted aryloxy, be substituted aryl, alkylthio, aminoacyl, aryl, be substituted amino, heteroaryl, heteroaryloxy ,-S (O) n-aryl, warp-S (O) n-substituted aryl ,-S (O) n-heteroaryl and warp-S (O) n-substituted heteroaryl, wherein n is 0,1 or 2.
R 1the better choosing group that freely following each base forms:
(3-p-methoxy-phenyl) sulfenyl;
(4-chloro-phenyl-) sulfenyl;
(4-aminomethyl phenyl) sulfenyl;
The 2-fluorophenoxy;
The 2-methoxyphenoxy;
(2-p-methoxy-phenyl) sulfenyl;
The 3-fluorophenoxy;
The 3-methoxyphenoxy;
4-(methyl carbonylamino) phenoxy group;
4-(methyl sulfonamido) phenoxy group;
The 4-fluorophenoxy;
The 4-methoxyphenoxy;
4-p-methoxy-phenyl sulfenyl;
The 4-aminomethyl phenyl;
Bromo;
Chloro;
Dimethylamino methyl;
Oxyethyl group;
The ethyl sulfenyl;
Hydrogen;
Sec.-propyl;
Methoxyl group;
Methoxymethyl;
Methyl;
N, N-dimethylamino carbonyl;
Naphthalene-2-base oxygen base;
The naphthyl sulfenyl;
Phenoxy group;
Phenyl;
Phenylamino;
The phenyl sulfinyl;
The phenyl sulfenyl;
Pyridine-2-base oxygen base;
Pyridine-2-base; With
Pyridine-2-base sulfenyl.
In the compound of formula I, IA, IB, IC and ID, R 2the better choosing group that freely following each base forms: be substituted amino, aryloxy, be substituted aryloxy, alkoxyl group, be substituted alkoxyl group, halogen, hydrogen, alkyl, be substituted alkyl, aryl ,-S (O) n-aryl, warp-S (O) n-substituted aryl ,-S (O) n-cycloalkyl, wherein n is 0,1 or 2, aminocarbonyl amino, heteroaryloxy and cycloalkyloxy.
R 2the better choosing group that freely following each base forms:
(4-methoxyl group) phenyl sulfonyl amino;
2,6-dimethyl phenoxy;
3,4-difluoro phenoxy group;
3,5-difluoro phenoxy group;
The chloro-4-fluorophenoxy of 3-;
3-methoxyl group-4-fluorophenoxy;
3-methoxyl group-5-fluorophenoxy;
4-(methyl sulfonamido) phenoxy group;
4-(phenyl sulfonamido) phenoxy group;
4-CF 3-O-phenoxy group;
4-CF 3-phenoxy group;
The 4-chlorophenoxy;
The 4-fluorophenoxy;
4-(4-fluorophenoxy) phenoxy group;
The 4-methoxyphenoxy;
4-nitrophenoxy;
Benzyloxy;
Bromo;
Butoxy;
CF 3；
Chloro;
Cyclohexyloxy;
The hexamethylene sulfenyl;
The cyclohexyl alkylsulfonyl;
Fluorine-based;
Hydrogen;
Iodo;
Isopropoxy;
Methyl;
Phenoxy group;
Phenyl;
The phenyl sulfenyl;
The phenyl sulfinyl;
Benzenesulfonyl;
Phenylurea;
Pyridine-1-base sulfenyl;
Pyridin-3-yl oxygen base; With
The pyridin-4-yl sulfenyl.
In the compound of formula I, IA, IB, IC and ID, R 3the better choosing group that freely following each base forms: be substituted aryloxy, be substituted alkoxyl group, alkoxyl group, be substituted alkyl, alkyl, amino, cycloalkyloxy, hydrogen, halogen, aryl ,-S (O) n-aryl, warp-S (O) n-substituted aryl ,-S (O) n-heteroaryl and warp-S (O) n-substituted heteroaryl, wherein n is 0,1 or 2, aminocarbonyl amino and heteroaryloxy.
R 3the better choosing group that freely following each base forms:
Amino;
(4-methyl) benzene fulfonic amide phenoxyl;
3,4-difluoro phenoxy group;
3,5-difluoro phenoxy group;
The fluoro-5-methoxyl group-phenoxy group of 3-;
The chloro-4-fluorophenoxy of 3-;
4-CF 3-O-phenoxy group;
4-CF 3-phenoxy group;
The 4-chlorophenoxy;
The 4-fluorophenoxy;
4-(4-fluorophenoxy) phenoxy group;
The 4-methoxyphenoxy;
Benzyloxy;
Bromo;
Butoxy;
CF 3；
Chloro;
Cyclohexyloxy;
Hydrogen;
Iodo;
Isopropoxy;
Phenoxy group;
Phenyl;
The phenyl sulfenyl;
Benzenesulfonyl;
The phenyl sulfinyl;
Phenylurea;
Pyridine-1-base sulfenyl;
Pyridin-3-yl oxygen base; With
The pyridin-4-yl sulfenyl.
Perhaps, R 2and R 3with side joint carbon atom combination thereon, and be connected to form aryl.Described aryl is preferably phenyl.
In the compound of formula I, IA, IB, IC and ID, R 4the better choosing group that freely following each base forms: be substituted arylthio, halogen, hydrogen, be substituted alkyl and aryl.
R 4the better choosing group that freely following each base forms:
(4-chloro-phenyl-) sulfenyl;
Chloro;
Hydrogen;
Methoxymethyl; With
Phenyl;
In the compound of formula I, IA, IB, IC and ID, R 5be preferably hydrogen or aryl.R 5be more preferred from hydrogen or phenyl.
In the compound of formula I, IA and IC, the group that the free hydrogen of the better choosing of R, deuterium, aryl and alkyl form.The group that the free phenyl of the better choosing of R, hydrogen, deuterium and methyl form.
In the compound of formula I, IA and IC, R' be selected from better by hydrogen, deuterium, alkyl, be substituted alkyl and be substituted the amino group formed.The better choosing of the R' group that freely following each base forms:
The 4-aminobutyl;
The 4-hydroxybenzyl;
Benzyl;
Carboxymethyl;
Deuterium;
Methylol;
The imidazol-4 yl methyl;
Sec.-propyl;
Methyl; With
Propyl group.
Perhaps, R and R' and side joint carbon atom thereon is connected to form cycloalkyl, is more preferred from cyclopropyl.
In the compound of formula I, IA and IC, R " is preferably hydrogen, alkyl or is substituted alkyl." better be hydrogen, methyl or carboxymethyl (CH to R 2c (O) OH).Perhaps, " and side joint carbon atom and nitrogen-atoms thereon is connected to form heterocyclic radical respectively, is more preferred from pyrrolidyl for R', R.
In the compound of formula I, IA, IB, IC and ID, R ' " the better choosing group that freely following each base forms: hydrogen, hydroxyl, alkoxyl group, be substituted alkoxyl group, cycloalkyloxy, be substituted cycloalkyloxy, thiol, acyloxy and aryl.R ' " the better choosing group that freely following each base forms:
Hydroxyl;
Benzyloxy;
Oxyethyl group;
Thiol;
Methoxyl group;
Methyl ketonic oxygen base; With
Phenyl.
In the compound of formula I, IB and IC, WR 8better choosing freely amino, be substituted the group that amino, aminoacyl, hydroxyl and alkoxyl group form.WR 8the better choosing group that freely following each base forms:
Amino;
Dimethylamino;
Hydroxyl;
Methoxyl group; With
The methyl carbonylamino.
Representative compound for described application is shown in Table A-D, wherein alphabetical corresponding to letter (that is, the representative compound of formula IA is in Table A) in structural formula in form.
Table A
Figure BDA00002247957200151
Figure BDA00002247957200152
Figure BDA00002247957200161
Figure BDA00002247957200171
Figure BDA00002247957200172
Figure BDA00002247957200181
Table B
Figure BDA00002247957200182
Sequence number R 2 R 3 WR 8
1 H H Methoxyl group
2 Isopropoxy H Amino
3 H Isopropoxy Methoxyl group
4 H H Amino
5 H H Hydroxyl
6 H Isopropoxy Hydroxyl
7 H H Dimethylamino
8 H H The methyl carbonylamino
9 H Isopropoxy Amino
10 H Isopropoxy Dimethylamino
11 Isopropoxy H Methoxyl group
12 Isopropoxy H Dimethylamino
13 Isopropoxy H Hydroxyl
Table C
Figure BDA00002247957200183
Sequence number R 2 R 3
1 Isopropoxy H
2 H Isopropoxy
3 H H
Table D
Figure BDA00002247957200192
Figure BDA00002247957200202
Figure BDA00002247957200211
Figure BDA00002247957200212
Figure BDA00002247957200241
Figure BDA00002247957200242
Be included in the interior compound of category of the present invention and comprise, for example the compound of following statement:
{ [4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(3-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(the fluoro-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(the fluoro-phenoxy group of 2-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(2-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(4-acetylaminohydroxyphenylarsonic acid phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(4-methanesulfonamido-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(4-hydroxyl-1-phenyl amino-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(1-chloro-4-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the chloro-4-oxyethyl group-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-oxyethyl group-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-oxyethyl group-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the chloro-4-phenyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methoxy methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-dimethylamino formyl radical-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-dimethylamino formyl radical-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-p-methylphenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [the chloro-7-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [the chloro-6-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(7-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(6-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(6-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(6-amino-4-hydroxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-7-(4-methoxyl group-phenylsulfonamido)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(4-hydroxyl-1-p-methylphenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-1-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(3-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(2-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(naphthalene-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(1-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-7-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(1-chloro-4-hydroxyl-6,7-bis-phenoxy groups-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-6,7-bis-phenoxy groups-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
(4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy group]-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid;
{ [4-hydroxyl-7-(4-nitro-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(4-sulfydryl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-sulfydryl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [7-(4-phenylsulfonamido-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-methanesulfonamido-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-trifluoromethoxy-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(4-trifluoromethoxy-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
2-(S)-{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-{[7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(R)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(R)-[(4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(4-sulfydryl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-{[1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
(R)-2-{[1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [7-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [the chloro-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [the bromo-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(the bromo-7-chloro-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(the bromo-6-chloro-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--6-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 1,7-bis--3-carbonyl)-amino]-acetic acid;
[(the bromo-1-chloro-4-hydroxyl-isoquinoline 99.9 of 7--3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 6--3-carbonyl)-amino]-acetic acid;
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of the bromo-7-of 1--3-carbonyl)-amino]-acetic acid;
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of 7--3-carbonyl)-amino]-acetic acid;
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of the chloro-7-of 1--3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-benzo [g] isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-ethyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-1-(4-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(the iodo-isoquinoline 99.9 of 1-chloro-4-hydroxyl-7--3-carbonyl)-amino]-acetic acid;
[(the iodo-isoquinoline 99.9 of 1-chloro-4-hydroxyl-6--3-carbonyl)-amino]-acetic acid;
[(the iodo-isoquinoline 99.9 of 4-hydroxyl-7--3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-7-butoxy of 1--4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-6-butoxy of 1--4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid;
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid;
[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid;
[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid;
[carboxymethyl-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[carboxymethyl-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-acetylaminohydroxyphenylarsonic acid ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid;
2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(lH-imidazol-4 yl)-propionic acid (three fluoro-acetates);
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(lH-imidazol-4 yl)-propionic acid (three fluoro-acetates);
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid;
(R)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(S)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(R)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(S)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(R)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(S)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate;
(S)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate;
(S)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
1-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropanecarboxylic acid;
1-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropanecarboxylic acid;
Two deuteriums-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
(R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
{ [7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
(7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid;
(6-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid;
{ [7-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
(S)-2-{[7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy group)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(6-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-cyclohexyloxy-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-isobutyl--isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-pyridine-2-base-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-ethyl-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid; With
Its pharmaceutically acceptable salt, ester and prodrug.
A kind of medical composition is provided in another embodiment of the present invention, and it comprises a kind of pharmaceutically acceptable vehicle or supporting agent and a kind of formula I compound of significant quantity or mixture of described compound for the treatment of.
The method of the patient's condition that also provides a kind for the treatment of, prevention or treatment in advance to be mediated by HIF and/or EPO at least partly.Described method comprises the compound with formula I structure that casts mammal patient treatment significant quantity, and restricted condition is the group that described compound does not select freely following material to form:
N-((1-chloro-4-hydroxyl-7-(2-propoxy-) isoquinoline 99.9-3-yl)-carbonyl)-glycine,
N-((1-chloro-4-hydroxyl-6-(2-propoxy-) isoquinoline 99.9-3-yl)-carbonyl)-glycine,
N-((1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino)-acetic acid,
N-((1-chloro-4-hydroxyl-7-methoxyl group isoquinoline 99.9-3-yl)-carbonyl)-glycine,
N-((1-chloro-4-hydroxyl-6-methoxyl group isoquinoline 99.9-3-yl)-carbonyl)-glycine,
N-((7-butoxy-1-chloro-4-hydroxyl isoquinoline 99.9-3-yl)-carbonyl)-glycine,
N-((6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino)-acetic acid,
N-((7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino)-acetic acid,
N-((8-chloro-4-hydroxyl isoquinoline 99.9-3-yl)-carbonyl)-glycine,
N-((7-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino)-acetic acid, and
((7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino) methyl acetate.
Another embodiment of the present invention provides the method for the hydroxylase activity of a kind of inhibition for regulating Hypoxia-inducible factor α subunit.
A kind of composition is also contained in the present invention, and it comprises other the mixture of therapeutic combination of formula I compound or formula I compound and at least one.Described other therapeutical agent is preferably erythropoietin.
The accompanying drawing explanation
Nothing
Embodiment
Before describing the present invention and method, should be appreciated that the present invention is not limited to described particular methodology, rules, clone, analysis and reagent, because these may change.Also should be appreciated that, term used herein is in order to describe specific embodiment of the present invention, and by no means in order to be limited in the category of the present invention of stating in additional claims.
Must be noted that, unless context separately has clearly indication, otherwise in literary composition and singulative " " and " described " of in additional claims, using comprise plural implication.
Unless otherwise defined, all technology used herein are identical with general the understood implication of those skilled in the art in the invention with scientific terminology.Although can use and similar or suitable any method and material described herein in practice of the present invention or test, describe now preferably method, equipment and material.For describing and disclosing in can the open case of use associated with the present invention methodology, reagent and the instrument of reporting, all open cases of quoting herein are incorporated herein by reference in full.This paper should be interpreted as the present invention and have the right to make described disclosure in advance because of previous invention.
Unless otherwise directed, practice of the present invention will be used chemistry, biological chemistry, molecular biology, cytobiology, genetics, immunology and the pharmacological method of the routine in affiliated technical field.Described technology is fully explained in document.(see, for example mark publishing company (Mack Publishing Co.) publish nineteen ninety by Gennaro, the 18th edition " Lei Shi pharmacy complete works " (Remington's Pharmaceutical Sciences) that A.R. edits; Academic press (Academic Press, Inc.) publish by Colowick, " Enzymology method " that the people such as S. edit (Methods In Enzymology); " experiment immunization handbook (Handbook of Experimental Immunology) the I-IV volume of being edited by D.M.Weir and C.C.Blackwell that " Backwill Science Press " (Blackwell Scientific Publications) published in 1986; " press of cold spring harbor laboratory " (Cold Spring Harbor Laboratory Press) in 1989, publish by Maniatis, " molecular cloning: laboratory manual " of the second edition that the people such as T. edit (Molecular Cloning:A Laboratory Manual) I-III volume; John Wei Li father and son (John Wiley&amp of publishing company; Sons) in 1999, publish by Ausubel, the 4th edition " the fine works molecular biology experiment guide " that the people such as F.M edit (Short Protocols in Molecular Biology); " Protocols in Molecular Biology: strengthening laboratory study course " (the Molecular Biology Techniques:An Intensive Laboratory Course) that edited by people such as Ream that academic press publishes in 1998; The 2nd edition PCR " biotechnology introduction book series " (Introduction to Biotechniques Series) edited by Newton and Graham that Springer Verlag Publishing Group (Springer Verlag) publishes in 1997.
Term used herein " anaemia " refers to cause any oxyphorase or red blood corpuscle that in blood, oxygen level reduces abnormal.Anaemia may be relevant with abnormal generation, processing or the performance of red blood corpuscle and/or oxyphorase.The term anaemia refers to any minimizing with respect to normal blood content of erythrocyte number in blood and/or content of hemoglobin.
Anaemia can be caused by patient's condition such as acute or chronic renal disease, infection, inflammation, cancer, irradiation, toxin, diabetes and operation.Infection can be caused by such as virus, bacterium and/or parasite etc.Inflammation can be caused by infection, autoimmune illness such as rheumatoid arthritis etc.Anaemia also may with lose blood relevantly, described losing blood can be caused by such as stomach ulcer, duodenal ulcer, hemorrhoid, cancer of the stomach or large bowel cancer, wound, damage, surgical procedure etc.Anaemia is further dialysed relevant with radiotherapy, chemotherapy and kidney.Anaemia is also relevant with the HIV infected patient that experiences Zidovodine (zidovudine (zidovudine)) or the treatment of other reverse transcriptase inhibitors, and can for example, in the cancer patients of experience chemotherapy (experiencing the cyclic chemical therapy that contains Platinol (cisplatin) or do not contain Platinol), occur.Aplastic anemia is the disease relevant with marrow failure with Myelodysplastic syndromes, and it can cause red blood corpuscle to produce minimizing.On the other hand, anaemia can be caused by defect or abnormal oxyphorase or red blood corpuscle, in the illness comprising microcytic anemia, hypochromic anemia etc.Anaemia can be caused by iron transfer, disposal and utilization imbalance, such as seeing sideroblastic anemia etc.
Term used " illness ", " disease " and " patient's condition " have the exhaustive implication, and refer to any normal situation that departs from.
Term " the anaemia patient's condition " is with " the anaemia illness " refers to any patient's condition relevant with anaemia, disease or illness.Described illness includes, but is not limited to above cited illness.The anaemia illness further includes, but is not limited to aplastic anemia, autoimmune hemolytic anemia, bone marrow transplantation, Qiu-Shi bis-syndromes (Churg-Strauss syndrome), diamond-Blackfan anemia (Diamond Blackfan anemia), anemia Fanconi's (Fanconi's anemia), the expense ear is carried syndrome (Felty syndrome), graft versus host disease (GVH disease), hemopoietic stem cell suppresses, hemolytic uremic syndrome, the development of bone marrow abnormal syndrome, nocturnal paroxysmal hemoglobinuria, osteomyelofibrosis, pancytopenia, pure red cell aplasia, purpura,Henoch-Schonlein (purpura Schoenlein-Henoch), sideroblastic anemia, increasing property of initiating cell refractory anemia, rheumatoid arthritis, Shu Wake Man syndromes (Shwachman syndrome), drepanocytosis, major thalaseemia, minor thalassemia, thrombopenic purpura etc.
Term " erythropoietin related conditions " be inclusive also refer to the relevant any patient's condition lower than normal, abnormal or improper adjusting with erythropoietin.The erythropoietin related conditions comprises increases any patient's condition that EPO content can provide the treatment benefit.The erythropoietin content relevant with the described patient's condition can be measured for the measuring method that the technician accepted and utilized in described field by any.The erythropoietin related conditions comprises the anaemia patient's condition, for example described above.
The erythropoietin related conditions further comprises neuroscience illness and/or damage, comprises the case of apoplexy, wound, epilepsy, neurodegenerative disease and similar disease, and wherein erythropoietin can provide neuroprotective.The neurodegenerative disease that the present invention is contained comprises Alzheimer's (Alzheimer's disease), Parkinson's disease (Parkinson's disease), Huntingtons chorea (Huntington's disease) and similar disease.
Term " erythropoietin " refers to any restructuring or spontaneous erythropoietin, comprises for example human erythropoietin (gene pool (GenBank) registration number AAA52400; The people such as Lin, (1985) " PNAS " 82:7580-7584}, EPOETIN human erythropoietin (Amgen, Inc., the oak city, California), ARANESP human erythropoietin (Amgen), PROCRIT human erythropoietin (Ortho Biotech Products, L.P., Raritan NJ) etc.
Term " HIF α " the alpha subunit that refers to hypoxia inducible factor albumen.HIF α can be any mankind or other mammalian proteins, or its segment, comprises human HIF-1-1 α (gene pool registration number Q16665), HIF-2 α (gene pool registration number AAB41495) and HIF-3 α (gene pool registration number AAD22668); Muridae HIF-1 α (gene pool registration number Q61221), HIF-2 α (gene pool registration number BAA20130 and AAB41496) and HIF-3 α (gene pool registration number AAC72734); Rat HIF-1 α (gene pool registration number CAA70701), HIF-2 α (gene pool registration number CAB96612) and HIF-3 α (gene pool registration number CAB96611); With ox HIF-1 α (gene pool registration number BAA78675).HIF α also can be any nonmammalian albumen or its segment, comprise Xenopus laevis (Xenopus laevis) HIF-1 α (gene pool registration number CAB96628), fruit rope (Drosophila melanogaster) HIF-1 α (gene pool registration number JC4851) and chicken HIF-1 α (gene pool registration number BAA34234).HIF α gene order also can obtain by conventional clone technology, for example, by the above-mentioned HIF α of all or part gene order is restored as probe and measured the HIF α gene order in another species.
The segment of HIF α comprises at least one function of reservation HIF α or any segment of constitutional features.The segment of HIF α comprises, such as defined as lower area by human HIF-1-1 α: amino acid 401 to the 603 (people such as Huang, above-mentioned), amino acid 531 to the 575 (people such as Jiang, (1997) " journal of biological chemistry " (J Biol.Chem), 272:19253-19260}, amino acid 556 to the 575 (people such as Tanimoto, above-mentioned), amino acid 557 to the 571 (people such as Srinivas, (1999) " biological chemistry and biophysical research communication ", 260:557-561}, with amino acid 556 to 575 (Ivan and Kaelin, (2001) " science " (Science), 292:464-468).On the other hand, HIF α segment comprises any segment that contains at least one motif LXXLAP, for example occurs in L in human HIF-1-1 α natural sequence 397tLLAP and L 559the EMLAP place.
The term that for example refers to HIF α and its fragment used herein " " contain oligopeptides, peptide or protein sequence, or refer to the segment of any these materials, and refer to that nature exists or synthetic molecules by aminoacid sequence "or" polypeptide." segment " can refer to retain any part of the sequence of at least one structure of albumen or functional character.Causing immune segment or antigene fragment is polypeptide fragments, is preferably length and is approximately 5 to 15 amino acid whose segments, and it retains at least one biology or immunologic competence.When " aminoacid sequence while having the peptide sequence of protein molecular " be used in reference to nature, " aminoacid sequence " and similar terms do not mean that aminoacid sequence is limited to the whole natural sequences relevant with cited protein molecular.
" associated protein " comprises other 2-oxoglutaric acid dioxygenase, especially similarly needs Fe the term that for example refers to HIF α prolyl hydroxylase associated protein used herein 2+, 2-oxoglutaric acid and oxygen to be to maintain the family member of hydroxylase activity.Described enzyme includes, but is not limited to, the asparaginyl hydroxylase that for example factor of procollagen lysyl hydroxylase, procollagen prolyl 4 hydroxylase and inhibition HIF (FIH), responsible adjusting HIF α activate mutually.(gene pool registration number AAL27308; The people such as Mahon, (2001) " gene and growth " (Genes Dev), 15:2675-2686; The people such as Lando, (2002) " science ", 295:858-861; With the people such as Lando, (2002) " gene and growth ", 16:1466-1471.Also see the people such as Elkins, (2002) " journal of biological chemistry " (J Biol Chem) C200644200 etc.).
Term " HIF prolyl hydroxylase " and " HIF PH " refer to any can hydroxylation HIF albumen in the enzyme of proline residue.By the better proline(Pro) of finding in motif LXXLAP that comprises of the hydroxylated proline residue of HIF PH, for example come across L397TLLAP and L559EMLAP place in human HIF-1-1 α natural sequence.HIF PH comprises by Taylor (2001, " gene " be 275:125-132 (Gene)) describe and by Aravind and Koonin (2001, " genome biology " (Genome Biol) 2:RESEARCH 0007), the people such as Epstein (2001, " cell " be 107:43-54 (Cell)) and Egl-Nine (EGLN) the gene family member that characterizes of Bruick and McKnight (2001, " science " 294:1337-1340).The example of HIF PH enzyme comprises mankind SM-20 (EGLN1) (gene pool registration number AAG33965; The people such as Dupuy (2000) " genomics " are 69:348-54 (Genomics)), EGLN2 isotype 1 (gene pool registration number CAC42510; Taylor, above-mentioned), EGLN2 isotype 2 (gene pool registration number NP_060025) and EGLN3 (gene pool registration number CAC42511; Taylor, above-mentioned); Mouse EGLN1 (gene pool registration number CAC42515), EGLN2 (gene pool registration number CAC42511) and EGLN3 (SM-20) (gene pool registration number CAC42517); With rat SM-20 (gene pool registration number AAA19321).In addition, HIF PH can comprise nematode (Caenorhabditis elegans) EGL-9 (gene pool registration number AAD56365) and drosophila melanogaster (Drosophila melanogaster) CG1114 gene product (gene pool registration number AAF52050).HIF PH also can comprise at least one structure of reservation of aforementioned full-length proteins or any segment of functional character.
Term " agonist " refers to a kind of molecule that increases or extend the duration of effect of specific molecular.Agonist can comprise that protein, nucleic acid, carbohydrate or any other increase the molecule of target molecule effect.
Term " antagonist " refers to a kind of biology or the degree of immunologic competence effect or molecule of time length that reduces specific molecular.Antagonist can comprise that protein, nucleic acid, carbohydrate, antibody or any other reduce the molecule of target molecule effect.
Term " microarray " refers to any arrangement of nucleic acid, amino acid, antibody etc. on matrix.Matrix can be any suitable supporter, such as bead, glass, paper, soluble cotton, nylon or any suitable film etc.Matrix can be any rigidity or semi-rigid supporter, includes, but is not limited to film, strainer, wafer, chip, slide glass, fiber, bead (comprising magnetic or nonmagnetic bead), gel, tubing, culture plate, polymkeric substance, particulate, kapillary etc.Matrix can be provided for the surface of coating and/or can have the kinds of surface form, and for example wellhole, pin, groove, passage and pore, make nucleic acid, amino acid etc. to be combined with described matrix.
Term used herein " vehicle " refers to inertia or the inactive substance used in medicinal product or other tablet manufacturing, includes, but is not limited to any material as tackiness agent, disintegrating agent, coating agent, compression/encapsulation auxiliary agent, newborn creme or lotion, lubricant, non-agent for enteron aisle, sweeting agent or spices, suspension/jelling agent or wet type granulating agent.Tackiness agent comprises such as carbopol (carbopol), Povidone, xanthan gum etc.; Coating agent comprises, such as cellulose acetate-phthalate, ethyl cellulose, gelling gum (gellan gum), maltodextrin etc.; Compression/encapsulation auxiliary agent, for example calcium carbonate, glucose, fructose dc, honey dc, lactose (anhydrous or monohydrate; Optionally with aspartame (aspartame), Mierocrystalline cellulose or Microcrystalline Cellulose combination), starch dc, sucrose etc.; Disintegrating agent comprises, such as croscarmellose sodium, gelling gum, carboxymethylstach sodium etc.; Breast creme or lotion comprise, such as maltodextrin, carrageenin etc.; Lubricant comprises, such as Magnesium Stearate, stearic acid, sodium stearyl fumarate etc.; For the material of chewable tablet, comprise, for example glucose, fructose dc, lactose (monohydrate; Optionally with aspartame or Mierocrystalline cellulose combination) etc.; The stomach external preparation comprises, such as N.F,USP MANNITOL, Povidone etc.; Softening agent comprises, such as Uniflex DBS, poly-phthalic acid vinyl acetate etc.; Suspension/jelling agent comprises, such as carrageenin, carboxymethylstach sodium, xanthan gum etc.; Sweeting agent comprises, such as aspartame, glucose, fructose dc, Sorbitol Powder, sucrose dc etc.; And the wet type granulating agent comprises, such as calcium carbonate, maltodextrin, Microcrystalline Cellulose etc.
Term used herein " loading dose " refers to the single or multiple doses that casts at first to reach rapidly required pharmacology content.For example, the loading dose of relevant the inventive method refers to rapidly for example plasma concentration of the compounds of this invention be increased to the initial dosage scheme of medicinal activity level.
Term used herein " inductive dose " refers to the repeated doses intensity that casts at first to reach rapidly required physiological responses.For example, the inductive dose of relevant the inventive method refers to rapidly hematocrit or hemoglobin level be increased to the initial dosage scheme in target zone, and described target zone can be normal plasma cell specific volume/hemoglobin level or lower than this level.
Term used herein " maintenance dose " refer to the load or inductive dose after cast in order to maintain the dosage level of required physiological responses.For example, the maintenance dose of relevant the inventive method refers to hematocrit and/or oxyphorase are maintained to the dosage in required target zone, and described target zone can be normal plasma cell specific volume/hemoglobin level or lower than this level.
Term used herein " sample " has broadest sense.Sample can be from any source, for example, from body fluid, secretory product, tissue, cell or culturing cell, include, but is not limited to saliva, blood, urine, serum, blood plasma, vitreum, synovia, cerebrospinal fluid, amniotic fluid and organ-tissue (for example biological tissue); From karyomit(e), organoid or other film by cellular segregation; From genomic dna, cDNA, RNA, mRNA etc.; With from scavenger cell or tissue or from trace or the marking of described cell or tissue.Sample also can be derived from any source, such as human experimenter or non-human mammal experimenter etc.Also contain the sample that is derived from any disease animal model.Sample can or can for example be fixed in solution on matrix or with its combination.Sample can refer to anyly be suitable for testing the material that erythropoietin or HIF α exist or refer to its segment, or any be suitable for screening increase erythropoietin or HIF α endogenous level molecule any material or refer to its segment.For obtaining the method for described sample within the state of the art in described field.
Term used herein " experimenter " has broadest sense.The experimenter can comprise protokaryon or eucaryon isolated cell, or cultivates the tissue of growing up.In certain embodiments, the experimenter is animal, the animal that particularly is selected from mammal, comprises rat, rabbit, Bovidae, sheep section, Suidae, Canidae, cat family, Muridae, equine and primates, the particularly mankind.
" alkyl " used herein refers to the monovalent alkyl with 1 to 10 carbon atom, is preferably to have 1 to 5 carbon atom and be more preferred to have 1 to 3 carbon atom.The example of this term is for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl and similar group.
Be substituted alkyl and refer to there is 1 to 5 substituting group, better 1 to 3 substituent 1 to 10 carbon atom, the alkyl of better 1 to 5 carbon atom, it independently selects the group that freely following each base forms: alkoxyl group, be substituted alkoxyl group, acyl group, amido, acyloxy, amino, be substituted amino, aminoacyl, aminocarbonyl amino, amino thio-carbonyl-amino, aminocarbonyl oxygen base, aryl, be substituted aryl, aryloxy, be substituted aryloxy, the aryloxy aryl, be substituted the aryloxy aryl, cyano group, halogen, hydroxyl, nitro, oxo, sulfo-, carboxyl, the carboxyl ester class, cycloalkyl, be substituted cycloalkyl, thiol, alkylthio, be substituted alkylthio, arylthio, be substituted arylthio, cycloalkylthio, be substituted cycloalkylthio, heteroarylthio, be substituted heteroarylthio, the heterocycle sulfenyl, be substituted the heterocycle sulfenyl, heteroaryl, be substituted heteroaryl, heterocycle, be substituted heterocycle, cycloalkyloxy, be substituted cycloalkyloxy, heteroaryloxy, be substituted heteroaryloxy, heterocyclic oxy group, be substituted heterocyclic oxy group, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-OS (O) 2-alkyl ,-OS (O) 2-be substituted alkyl ,-OS (O) 2-aryl ,-OS (O) 2-be substituted aryl ,-OS (O) 2-heteroaryl ,-OS (O) 2-be substituted heteroaryl ,-OS (O) 2-heterocycle ,-OS (O) 2-be substituted heterocycle ,-OSO 2-NR 40r 40(each R wherein 40for hydrogen or alkyl) ,-NR 40s (O) 2-alkyl ,-NR 40s (O) 2-be substituted alkyl ,-NR 40s (O) 2-aryl ,-NR 40s (O) 2-be substituted aryl ,-NR 40s (O) 2-heteroaryl ,-NR 40s (O) 2-be substituted heteroaryl ,-NR 40s (O) 2-heterocycle ,-NR 40s (O) 2-be substituted heterocycle ,-NR 40s (O) 2-NR 40-alkyl ,-NR 40s (O) 2-NR 40-be substituted alkyl ,-NR 40s (O) 2-NR 40-aryl ,-NR 40s (O) 2-NR 40-be substituted aryl ,-NR 40s (O) 2-NR 40-heteroaryl ,-NR 40s (O) 2-NR 40-be substituted heteroaryl ,-NR 40s (O) 2-NR 40-heterocycle, and-NR 40s (O) 2-NR 40-be substituted heterocycle, wherein each R 40for hydrogen or alkyl.
" alkoxyl group " refers to " alkyl-O-", and the example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy and similar group.
" be substituted alkoxyl group " and refer to " being substituted alkyl-O-" base.
" acyl group " refer to H-C (O)-, alkyl-C (O)-, be substituted alkyl-C (O)-, thiazolinyl-C (O)-, be substituted thiazolinyl-C (O)-, alkynyl-C (O)-, be substituted alkynyl-C (O)-, cycloalkyl-C (O)-, be substituted cycloalkyl-C (O)-, aryl-C (O)-, be substituted aryl-C (O)-, heteroaryl-C (O)-, be substituted heteroaryl-C (O), heterocycle-C (O)-and be substituted heterocycle-C (O)-, the nitrogen-atoms that restricted condition is heterocycle or is substituted heterocycle is not combined with-C (O)-Ji, alkyl wherein, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle as defined herein.
Refer to-C of prefix (O) NR of term " aminoacyl " or " carbamyl " or " carboxamide " or " being substituted carbamyl " or " being substituted carboxamide " 42r 42base, wherein each R 42the independent choosing group that freely following each base forms: hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocycle, be substituted heterocycle and each R wherein 42be connected to form heterocycle with nitrogen-atoms or be substituted heterocycle, wherein alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle as defined herein.
" acyloxy " refers to alkyl-C (O) O, be substituted alkyl-C (O) O-, thiazolinyl-C (O) O-, be substituted thiazolinyl-C (O) O-, alkynyl-C (O) O, be substituted alkynyl-C (O) O-, aryl-C (O) O-, be substituted aryl-C (O) O-, cycloalkyl-C (O) O-, be substituted cycloalkyl-C (O) O-, heteroaryl-C (O) O-, be substituted heteroaryl-C (O) O-, heterocycle-C (O) O-and be substituted heterocycle-C (O) O-, alkyl wherein, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle as defined herein.
" thiazolinyl " refers to goodly have 2 to 6 carbon atoms, and goodly has 2 to 4 carbon atoms and have at least 1, the thiazolinyl of better 1 to 2 unsaturated position of thiazolinyl.
" be substituted thiazolinyl " and refer to have 1 to 3 substituting group and better 1 to 2 substituent thiazolinyl, its choosing group that freely following each base forms: alkoxyl group, be substituted alkoxyl group, acyl group, amido, acyloxy, amino, be substituted amino, aminoacyl, aryl, be substituted aryl, aryloxy, be substituted aryloxy, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxyl ester class, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle.
" alkynyl " refers to goodly have 2 to 6 carbon atoms, and the better alkynyl that has 2 to 3 carbon atoms and have at least 1 and better 1 to-2 unsaturated position of alkynyl.
" be substituted alkynyl " and refer to have 1 to 3 substituting group and better 1 to 3 substituent alkynyl, its choosing group that freely following each base forms: alkoxyl group, be substituted alkoxyl group, acyl group, amido, acyloxy, amino, be substituted amino, aminoacyl, aryl, be substituted aryl, aryloxy, be substituted aryloxy, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxyl ester class, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle.
" amino " refer to-NH 2base.
Refer to-the NR that " is substituted amino " 41r 41base, wherein each R 41base independently selects the group that freely following each base forms: hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle, be substituted heterocycle ,-SO 2-alkyl ,-SO 2-be substituted alkyl ,-SO 2-thiazolinyl ,-SO 2-be substituted thiazolinyl ,-SO 2-cycloalkyl ,-SO 2-be substituted cycloalkyl ,-SO 2-aryl ,-SO 2-be substituted aryl ,-SO 2-heteroaryl ,-SO 2-be substituted heteroaryl ,-SO 2-heterocycle ,-SO 2-being substituted heterocycle, restricted condition is R 41base is not all hydrogen; Or R 41base can be connected to form heterocycle or be substituted heterocycle with nitrogen-atoms.
" amido " refer to-NR 45c (O) alkyl ,-NR 45c (O) be substituted alkyl ,-NR 45c (O) cycloalkyl ,-NR 45c (O) be substituted cycloalkyl ,-NR 45c (O) thiazolinyl ,-NR 45c (O) be substituted thiazolinyl ,-NR 45c (O) alkynyl ,-NR 45c (O) be substituted alkynyl ,-NR 45c (O) aryl ,-NR 45c (O) be substituted aryl ,-NR 45c (O) heteroaryl ,-NR 45c (O) be substituted heteroaryl,
-NR 45c (O) heterocycle and-NR 45c (O) is substituted heterocycle, wherein R 45be hydrogen or alkyl and wherein alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle as defined herein.
" carbonyl oxygen base amino " refers to-NR 46c (O) O-alkyl ,-NR 46c (O) O-be substituted alkyl ,-NR 46c (O) O-thiazolinyl ,-NR 46c (O) O-be substituted thiazolinyl ,-NR 46c (O) O-alkynyl ,-NR 46c (O) O-be substituted alkynyl ,-NR 46c (O) O-cycloalkyl ,-NR 46c (O) O-be substituted cycloalkyl ,-NR 46c (O) O-aryl ,-NR 46c (O) O-be substituted aryl ,-NR 46c (O) O-heteroaryl ,-NR 46c (O) O-be substituted heteroaryl ,-NR 46c (O) O-heterocycle and-NR 46c (O) O-is substituted heterocycle, wherein R 46be hydrogen or alkyl and wherein alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle as defined herein.
Refer to-OC of prefix (O) NR of " aminocarbonyl oxygen base " or " carbamyl oxygen base " or " being substituted carbamyl oxygen base " 47r 47base, wherein each R 47independent for hydrogen, alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle or each R wherein 47be connected to form heterocycle with nitrogen-atoms or be substituted heterocycle, and wherein alkyl, be substituted alkyl, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle as defined herein.
" aminocarbonyl amino " refers to-NR 49c (O) NR 49-Ji, wherein R 49it is the group that selects free hydrogen and alkyl to form.
" aryl " or " virtue " refers to the monovalent aromatic carbocylic radical of 6 to 14 carbon atoms, it has monocycle (for example phenyl) or polynary condensed ring (for example naphthyl or anthryl), described condensed ring can be or can be not for aromatic nucleus (for example, 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H)-one-7-base and similar group thereof), restricted condition is that tie point is aryl.Better phenyl and the naphthyl of comprising of aryl.
" be substituted aryl " and refer to that aryl is by 1 to 4 as defined herein, the substituting group that each base below better 1 to 3 choosing freely forms group replaces: hydroxyl, acyl group, amido, the carbonylamino sulfenyl, acyloxy, alkyl, be substituted alkyl, alkoxyl group, be substituted alkoxyl group, thiazolinyl, be substituted thiazolinyl, alkynyl, be substituted alkynyl, amidino groups, amino, be substituted amino, aminoacyl, aminocarbonyl oxygen base, aminocarbonyl amino, amino thio-carbonyl-amino, aryl, be substituted aryl, aryloxy, be substituted aryloxy, cycloalkyloxy, be substituted cycloalkyloxy, heteroaryloxy, be substituted heteroaryloxy, heterocyclic oxy group, be substituted heterocyclic oxy group, carboxyl, the carboxyl ester class, cyano group, thiol, alkylthio, be substituted alkylthio, arylthio, be substituted arylthio, heteroarylthio, be substituted heteroarylthio, cycloalkylthio, be substituted cycloalkylthio, the heterocycle sulfenyl, be substituted the heterocycle sulfenyl, cycloalkyl, be substituted cycloalkyl, guanidine radicals, halogen, nitro, heteroaryl, be substituted heteroaryl, heterocycle, be substituted heterocycle, oxygen base carbonylamino, oxygen base thio-carbonyl-amino,-S (O) 2-alkyl ,-S (O) 2-be substituted alkyl ,-S (0) 2-cycloalkyl ,-S (O) 2-be substituted cycloalkyl ,-S (O) 2-thiazolinyl ,-S (O) 2-be substituted thiazolinyl ,-S (O) 2-aryl ,-S (O) 2-be substituted aryl ,-S (O) 2-heteroaryl ,-S (O) 2-be substituted heteroaryl ,-S (O) 2-heterocycle ,-S (O) 2-be substituted heterocycle ,-OS (O) 2-alkyl ,-OS (O) 2-be substituted alkyl ,-OS (O) 2-aryl ,-OS (O) 2-be substituted aryl ,-OS (O) 2-heteroaryl ,-OS (O) 2-be substituted heteroaryl ,-OS (O) 2-heterocycle ,-OS (O) 2-be substituted heterocycle ,-OSO 2-NR 51r 51each R wherein 51for hydrogen or alkyl ,-NR 51s (O) 2-alkyl ,-NR 51s (O) 2-be substituted alkyl ,-NR 51s (O) 2-aryl ,-NR 51s (O) 2-be substituted aryl ,-NR 51s (O) 2-heteroaryl ,-NR 51s (O) 2-be substituted heteroaryl ,-NR 51s (O) 2-heterocycle ,-NR 51s (O) 2-be substituted heterocycle ,-NR 51s (O) 2-NR 51-alkyl ,-NR 51s (O) 2-NR 51-be substituted alkyl ,-NR 51s (O) 2-NR 51-aryl ,-NR 51s (O) 2-NR 51-be substituted aryl ,-NR 51s (O) 2-NR 51-heteroaryl ,-NR 51s (O) 2-NR 51-be substituted heteroaryl ,-NR 51s (O) 2-NR 51-heterocycle and-NR 51s (O) 2-NR 51-be substituted heterocycle, wherein each R 51for hydrogen or alkyl, wherein each term as defined herein.
" aryloxy " refers to aryl-O-base, and the example comprises phenoxy group, naphthyloxy and similar group thereof.
" be substituted aryloxy " and refer to be substituted aryl-the O-base." aryloxy aryl " refer to-aryl-O-aryl.
" be substituted the aryloxy aryl " and refer to as the above-mentioned definition for being substituted aryl, by 1 to 3 substituting group one or two fragrant nuclear substituted aryloxy aryl in office.
" carboxyl " refer to-COOH or its salt.
" carboxyl ester class " refer to-C (O) O-alkyl ,-C (O) O-be substituted alkyl ,-C (O) O-aryl and-C (O) O-is substituted aryl, wherein alkyl, be substituted alkyl, aryl and be substituted aryl as defined herein.
" cycloalkyl " refers to have the cycloalkyl of 3 to 10 carbon atoms of single or polynary ring, and the example comprises adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group and similar group thereof.
" be substituted cycloalkyl " and refer to have 1 to 5 substituent cycloalkyl, the described substituting group choosing group that freely following each base forms: ketone group (=0), thioketones base (=S), alkoxyl group, be substituted alkoxyl group, acyl group, amido, acyloxy, amino, be substituted amino, aminoacyl, aryl, be substituted aryl, aryloxy, be substituted aryloxy, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxyl ester class, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted heterocycle.
" cycloalkyloxy " refer to-O-cycloalkyl.
Refer to-O-is substituted cycloalkyl " to be substituted cycloalkyloxy ".
" halogen " or " halogen " refers to fluorine-based, chloro, bromo and iodo and is preferably fluorine-based or chloro.
" heteroaryl " refers to have 1 to 15 carbon atom, and in better 1 to 10 carbon atom and ring, 1 to 4 is selected from the heteroatomic aromatic base that oxygen, nitrogen and sulphur form group.Described heteroaryl can have monocycle (for example pyridyl or furyl) or polynary fused rings (for example indolizine base or benzothienyl).Preferably heteroaryl comprises pyridyl, pyrryl, indyl, thienyl and furyl.
" be substituted heteroaryl " and refer to the heteroaryl replaced by 1 to 3 substituting group, described substituting group be selected from be substituted aryl in the identical group of defined substituting group.
" heteroaryloxy " refer to-O-heteroaryl and " being substituted heteroaryloxy " refer to-O-are substituted heteroaryl.
" heterocycle " refers to have monocycle or polynary ring filling or the unsaturated group of condensing, it has 1 to 4 heteroatoms that is selected from nitrogen, sulphur and oxygen composition group in 1 to 10 carbon atom and ring, wherein in carbocyclic fused ring system, one or more ring can be aryl or heteroaryl, and restricted condition is that tie point is on heterocycle.
" be substituted heterocycle " and refer to the heterocycle replaced by 1 to 3 substituting group, described substituting group be substituted cycloalkyl in defined substituting group identical.
The example of heterocycle and heteroaryl includes, but is not limited to azetidine, the pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indoline, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, naphthyl pyridine (naphthylpyridine), quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene, isoxazole, phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1, 2, 3, the 4-tetrahydro-isoquinoline, 4, 5, 6, 7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thio-morpholinyl (thiomorpholinyl) (being also referred to as (thiamorpholinyl)), piperidyl, tetramethyleneimine, tetrahydrofuran base and similar group thereof.
" heterocyclic oxy group " refer to-O-heterocycle and " being substituted heterocyclic oxy group " refer to-O-are substituted heterocycle.
" thiol " or " sulfydryl " refer to-SH base.
" alkylthio " refer to-S-alkyl, wherein alkyl as defined above.
Refer to as defined above-S-is substituted alkyl " to be substituted alkylthio ".
" cycloalkylthio " refer to-S-cycloalkyl, wherein cycloalkyl as defined above.
Refer to-S-is substituted cycloalkyl " to be substituted cycloalkylthio ", wherein is substituted cycloalkyl as defined above.
" arylthio " refer to-S-aryl and " being substituted arylthio " refer to-S-are substituted aryl, wherein aryl and be substituted aryl as defined above.
" heteroarylthio " refer to-S-heteroaryl and " being substituted heteroarylthio " refer to-S-are substituted heteroaryl, wherein heteroaryl and be substituted heteroaryl as defined above.
" heterocycle sulfenyl " refer to-S-heterocycle and " being substituted the heterocycle sulfenyl " refer to-S-are substituted heterocycle, wherein heterocycle and be substituted heterocycle as defined above.
Term " amino acid " refers to that (for example there is amino acid whose D-steric isomer in any amino acid and synthetic analogues naturally existed naturally, D-Thr for example) and its derivative, a-amino acid comprises a carbon atom, is connected with an amino, a carboxyl, a hydrogen atom and a characteristic group that is called as " side chain " on it.Naturally exist amino acid whose side chain to be known by us in technique, for example hydrogen (for example, in glycine), alkyl (for example, in L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, proline(Pro)), be substituted alkyl (for example, in Threonine, Serine, methionine(Met), halfcystine, aspartic acid, l-asparagine, L-glutamic acid, glutamine, arginine and Methionin), arylalkyl (for example, in phenylalanine and tryptophane), be substituted arylalkyl (for example, in tyrosine) and heteroarylalkyl (for example, in Histidine).Non-natural amino acid is also known in technique, " synthesizing of optical activity alpha-amino acid " (the Synthesis of Optically Active.alpha.-Amino Acids) that edited by Williams that for example Pei Geman publishing company (Pergamon Press) publishes in 1989; The people such as Evans, " american Journal of the Chemical Society " (J.Amer.Chem.Soc.), 112:4011-4030 (1990); The people such as Pu, " american Journal of the Chemical Society ", 56:1280-1283 (1991); The people such as Williams, " american Journal of the Chemical Society ", state in 113:9276-9286 (1991); With all documents of wherein quoting.The present invention also comprises non-naturally amino acid whose side chain.
" pharmaceutically acceptable salt " refers to the pharmaceutically acceptable salt of compound, described salt is that to be derived from multiple technique be our known organic and inorganic counter ion, and it comprises (only as an example) sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium and similar group thereof; And when described molecule contains basic functionality, its salt that is organic or inorganic acid, for example hydrochloride, hydrobromate, tartrate, mesylate, acetate, maleate, oxalate and its class are saloid.
Term " prerequisite medicine " thus refer to the compounds of this invention that comprises physiology and biocompatible removable group through modifying, described group removes to provide active medicine, its pharmaceutically acceptable salt or its bioactive metabolites in vivo.Suitable removable group is known for us in technique and better removable group comprises the ester of carboxylic moiety on the glycine substituting group.Described ester class is better to be comprised derived from the alkyl alcohols, be substituted the ester of alkyl alcohols, hydroxyl substituted aryl and heteroaryl etc.Another better removable group is the acid amides formed by the carboxylic moiety on the glycine substituting group.Suitable acid amides is derived from formula HNR 20r 21amine, R wherein 20and R 21be independently hydrogen, alkyl, be substituted alkyl, aryl, be substituted aryl and similar group thereof.
Should be appreciated that in all substituting groups defined above, there is the polymkeric substance that the substituting group that is same as in addition self obtains and (for example there is one and be substituted aryl as the substituent aryl that is substituted by substituting group is defined as, himself by one, be substituted aryl and replace, etc.) and be not included in herein.In said case, described substituent maximum number is 3.That is to say, each above-mentioned definition is retrained by a restriction, for example is substituted aryl and is limited to-is substituted aryl-(being substituted aryl)-be substituted aryl.
Should be appreciated that equally above-mentioned definition is not in order to comprise unallowed substitute mode (for example, with 5 fluorine-based substituent methyls or the hydroxyl that is the α position with respect to ethene or acetylene unsaturated link(age)).The technician that the substitute mode of described permission is described field is known.
Method of the present invention
The invention provides the method for regulating HIF and/or EPO, thus its expression of by suppressing HIF α hydroxylation, stablizing HIF and activating the HIF regulatory gene.Described method also can be applicable to prevention, treatment in advance or treatment HIF and/or EPO related conditions, comprises anaemia, local asphyxia and the anoxic patient's condition.
The treatment of HIF related conditions
Local asphyxia is two kinds of patient's condition relevant with HIF with anoxic and includes, but is not limited to myocardial infarction, liver local asphyxia, kidney local asphyxia and apoplexy; Surrounding blood vessel illness, ulcer, burn and chronic wounds; Pulmonary infarction; And ischemia reperfusion injury, comprise for example relevant to operation and organ transplantation ischemia reperfusion injury.In one embodiment, the invention provides before local asphyxia or anoxic, among or stablize immediately afterwards the method, particularly local asphyxia or the anoxic relevant with myocardial infarction, apoplexy or Renal Ischemia Reperfusion Injury of HIF α.
One aspect of the present invention is provided for treating the method for multiple local asphyxia and the anoxic patient's condition, particularly uses compound described herein.In one embodiment, when casting after local asphyxia or anoxic, method of the present invention produces the treatment benefit.For example, after myocardial infarction, method of the present invention makes the reduction that M & M is surprising, and significantly improves cardiac structure and performance.On the other hand, when casting after hepatogenotoxicity-ischemic injury, method of the present invention is improved liver function.Anoxic is an important component part of hepatic diseases, especially with the liver toxicity compound, for example, in the relevant chronic hepatopathy of ethanol.In addition, known genetic expression of being induced by HIF α increases in alcoholic liver disease, for example nitric oxide synthetase and glucose transporter-1.(see, such as people such as Areel, (1997) " hepatology " be 25:920-926 (Hepatology); Strubelt, (1984) " basis and applied toxicology " be 4:144-151 (Fundam.Appl.Toxicol.); Sato, (1983) " pharmacology, biological chemistry and behavior " (Pharmacol Biochem Behav) 18 (supplementary issue l): 443-447; The people such as Nanji, (1995) " American Journal of Pathology " be 146:329-334 (Am.J.Pathol.); With people such as Morio, (2001) " toxicology and drug application " be 172:44-51 (Toxicol.Appl.Pharmacol.)).
Therefore, the invention provides the method for the treatment of local asphyxia or anoxic related conditions, described method comprises by the compound for the treatment of significant quantity or its pharmaceutically acceptable salt separately or cast the experimenter with pharmaceutically acceptable excipient composition.In one embodiment, cast immediately described compound after producing the ischemic patient's condition, for example myocardial infarction, pulmonary infarction, intestinal obstruction, ishemic stroke and Renal Ischemia Reperfusion Injury.In another embodiment, described compound is cast to the patient who is diagnosed as the patient's condition relevant to chronic ischemic generation, for example cardiac cirrhosis, macular degeneration, pulmonary infarction, acute respiratory failure, congenital alveolar dysplasia and congestive heart failure.In another embodiment, cast immediately described compound after wound or damage.
Another aspect of the present invention provides the method for using compounds for treating described herein that the patient that local asphyxia or the danger of the anoxic patient's condition occur is arranged, for example atherosclerosis high-risk individuals.Atherosclerotic Hazard Factor comprise, for example hyperlipidaemia, smoking, hypertension, diabetes, hyperinsulinemia and abdominal obesity.Therefore, the invention provides the method for prevention ischemic tissue injury, described method comprises the compound for the treatment of significant quantity or its pharmaceutically acceptable salt is cast to the patient of needs separately or with pharmaceutically acceptable excipient composition.In one embodiment, can cast described compound based on procatarxis venereal disease condition, for example hypertension, diabetes, arteriosclerosis obliterans, chronic venous insufficiency, Raynaud disease, chronic skin ulcer, sclerosis, congestive heart failure and systemic sclerosis.
In a particular embodiment, described method is formed for increasing the vascularization in damaged tissue, wound and ulcer and/or granulation tissue.For example, but compound of the present invention has been presented in wound healing the effective stimulus granulation tissue forms.The seepage blood vessel that granulation tissue contains new formation and interim plasma proteins matrix, for example Fibrinogen and plasma fibronectin.Release from the somatomedin of inflammatory cell, thrombocyte and activation endothelium stimulates inoblast and migration and the propagation of endotheliocyte in granulation tissue.If vascularization or nerve stimulation weaken, ulcer can occur.Method of the present invention effectively promotes the formation of granulation tissue.Thereby, the invention provides to be used for the treatment of and have due to tissue damage that for example infraction causes, have by the wound of for example wound or wound inducement or there is for example, method due to certain illness (diabetes) chronic wounds produced or the patient of ulcer.Described method comprises the treatment compound of significant quantity or its pharmaceutically acceptable salt is cast to the patient of needs separately or with pharmaceutically acceptable excipient composition.
Another aspect of the present invention provides and uses described compound to treat in advance the method that the experimenter occurs with minimizing or the prevention tissue damage relevant to local asphyxia or anoxic.While casting immediately before the patient's condition that is relating to local asphyxia or anoxic, method of the present invention produces the treatment benefit.For example, before inducing myocardial infarction, application method of the present invention shows that cardiac structure and performance obtain the improvement of significance statistically.On the other hand, when before ischemia reperfusion injury and between while casting immediately, method of the present invention produces the treatment benefit, significantly reduces the Diagnostic parameters relevant to renal failure.
Therefore, the invention provides and treat in advance the method for experimenter with minimizing or the prevention tissue damage relevant to local asphyxia or anoxic, described method comprises by the treatment compound of significant quantity or its pharmaceutically acceptable salt separately or cast the patient with ischemic conditions medical history with pharmaceutically acceptable excipient composition, myocardial infarction for example, or there is the patient of approaching ischemic conditions, for example stenocardia.In another embodiment, can may ischemic physical parameter cast described compound based on hint, for example, under general anesthesia or the individuality of temporarily working under high height above sea level.In another embodiment, can be by described compound for organ transplantation, in order to treating organs donor in advance or before being implanted into acceptor, in order to maintain the organ removed from health.
Previous research shows, some compound used in the method for the invention is effective inhibitor of procollagen prolyl 4 hydroxylase.Although recognize that the recovery of initial infraction or wound needs reticular tissue to deposit in necrotic zone, the present invention's proof has no side effect for synulotic treatment.Thereby, the benefit provided on treatment and the damage of prevention oxygen-starved tissue and fibrosis based on some compound of the present invention, the present invention is contained a kind for the treatment of or is prevented to relate to " double treatment " method of local asphyxia or the anoxic patient's condition, comprise local asphyxia or the anoxic relevant to the concurrent reaction fibrosis, for example myocardial infarction and consequent congestive heart failure.Described method can be used a kind of compound, and it suppresses more than one and has phase homospecificity or not homospecific 2-oxoglutaric acid dioxygenase, for example HIF prolyl hydroxylase and procollagen prolyl 4 hydroxylase.Perhaps, described method can be used the combination of compound, only a kind of 2-oxoglutaric acid dioxygenase, for example special inhibition of a kind of compound HIF prolyl hydroxylase and the special inhibition procollagen of the second compound prolyl 4 hydroxylase of the special inhibition of each compound wherein.
In one aspect, compound of the present invention suppresses one or more 2-oxoglutaric acid dioxygenases.In one embodiment, described compound suppresses at least two kinds and has phase homospecificity or not homospecific 2-oxoglutaric acid dioxygenase family member, for example HIF prolyl hydroxylase and HIF l-asparagine-hydroxylase (FIH-1).In another embodiment, described compound has specificity for a kind of 2-oxoglutaric acid dioxygenase, HIF prolyl hydroxylase for example, and demonstrate specificity seldom or do not show specificity for other family member.
Described compound can cast with multiple other methods for the treatment of combination.In one embodiment, described compound casts together with another kind of 2-oxoglutaric acid dioxygenase inhibitor, and wherein these two kinds of compounds have different specificitys for individual other 2-oxoglutaric acid dioxygenase family member.Described two kinds of compounds can cast with a ratio with respect to another simultaneously.Within the state of the art that is determined at described field for the ratio that is suitable for given therapeutic process or particular subject.Perhaps, described two kinds of compounds can cast continuously in the treatment time-histories, for example, after myocardial infarction.In a particular embodiment, the activity of the special inhibition of a kind of compound HIF prolyl hydroxylase, and the activity of the special inhibition procollagen of the second compound prolyl 4 hydroxylase.In another specific embodiment, the activity of the special inhibition of a kind of compound HIF prolyl hydroxylase, and the activity of the special inhibition of the second compound HIF asparaginyl-hydroxylase.In another embodiment, described compound casts together from the therapeutical agent that another has different binding modes, such as ACE inhibitor (ACEI), AngiotensionⅡ receptor blocking agent (ARB), statin, diuretic(s), digoxin, carnitine etc.
The treatment of EPO related conditions
The invention provides the method that increases endogenous erythropoietin (EPO).These methods can be applied in vivo, for example, in blood plasma, or application in vitro, for example, in the cell culture medium through regulating.The present invention further provides the method that increases endogenous EPO content, in order to prevention, treatment in advance or treatment EPO related conditions, comprise for example relevant to anaemia and the neurological disorder patient's condition.The anaemia related conditions comprises the illness such as acute or chronic renal disease, diabetes, cancer, ulcer, virus infection (such as HIV, bacterium or parasite), inflammation etc.The anaemia patient's condition can further comprise to program or treat the relevant patient's condition, and described program or treatment comprise for example radiotherapy, chemotherapy, dialysis and operation.The anaemia associated conditions comprises abnormal haemoglobin and/or red blood corpuscle in addition, such as being found in as in the illnesss such as microcytic anemia, hypochromic anemia, aplastic anemia.
The present invention can be used for preventative or increases the endogenous EPO in the experimenter of experience particular treatment or program simultaneously, for example just with the infected by HIV anaemia patient of zidovudine or the treatment of other reverse transcriptase inhibitors, accept containing ring Platinol (cisplatin) or not containing the anaemia cancer patients of the cyclic chemical therapy of Platinol or anaemia or the non-anaemia patient of plan experience operation.The method that increases endogenous EPO also can be used for prevention, treatment in advance or treatment and the EPO related conditions that nerve damages or nervous tissue is degenerated relevant, includes, but is not limited to apoplexy, wound, epilepsy, Spinal injury and neurodegenerative disorders.
In addition, described method can be used for the anaemia of increase plan experience operation or the endogenous EPO content in non-anaemia patient, in order to reduce to the needs of external source blood transfusion or with so that the storage of the front blood of operation.A small amount of minimizing of the blood hematocrit usually occurred after autologous blood supply before operation is stimulation of endogenous EPO or compensatory erythropoietic increase not.Yet thorn is goaded effective increase red blood corpuscle quality and autologous blood supply volume into action before the operation of endogenous EPO, maintains higher hematocrit levels simultaneously, and described method is specific is covered by herein.In some operation crowds, particularly operation is lost blood and is surpassed the individuality of 2 liters, can apply method of the present invention and reduce allos blood and expose to the open air.Crosby (2002) " U.S.'s therapeutics magazine " is 9:371-376 (Amer.J.Therap.).
Method of the present invention also can be used for strengthening exercise performance, improves exercising ability and promotion or strengthen aerobic and regulate.For example, the sportsmen can use described method to promote training and soldier can use described method to improve for example stamina and endurance.
Method of the present invention shown in the substratum that can increase the external treatment culturing cell and the animal plasma of interior therapeutic in endogenous erythropoietin content.Although kidney is the main source of erythropoietin in body, once suitable stimulation, other organ, comprise that brain, liver and marrow can and really can synthesize erythropoietin.Use method of the present invention can increase the expression of endogenous erythropoietin in a plurality of body members, comprise brain, kidney and liver.In fact, method of the present invention even is increased in the content of endogenous erythropoietin in the two animals of surveying nephrectomies of experience.
Even method proof of the present invention, when kidney function damage, also can increase the content of erythropoietin.Although the present invention is not limited by the mechanism that erythropoietin produces, the hyperoxia that the minimizing of visible erythropoietin secretion is flowed/poured into due to increasing in being attributable to nephridial tissue in the renal failure process usually.The people such as Priyadarshi, (2002) " international kidney magazine " (Kidney Int.) 61:542-546.
On the other hand, hematocrit and blood hemoglobin level in the animal of method increase interior therapeutic of the present invention.Along with compound is used and the increase of the blood plasma EPO, hematocrit and the blood oxyphorase that produce has dosage susceptibility in the method for the invention, yet can determine that dosage is to produce the level of response of constant, controlled the compounds of this invention.On the other hand, use the treatment of the compounds of this invention can cure anaemia, for example, by toxic chemical, the anaemia that for example the chemotherapeutic Platinol is induced, or for example, due to the anaemia due to losing blood, wound, damage, parasite or operation.
In animal with compounds for treating of the present invention, before hematocrit and the increase of blood oxyphorase, be the percentile increase of immature erythrocyte (reticulocyte) that circulates in blood.Thereby, thereby the purposes in the method that the content of the compounds of this invention reticulocyte in increasing animal blood produces acellular reticulocyte lysate (as Pelham and Jackson at " european journal of biological chemistry " (Eur.J.Biochem.) described in 67:247-256 (1976)) is contained in the present invention.By with compound of the present invention separately treatment or with another kind of compound, such as combined therapies such as pyrodins, in animal (such as rabbit etc.), circulating net is knitted erythrocytic content increases.Collect blood, and make the reticulocyte globulate and make cytolysis with distilled water by centrifugal.Extract can be known with any those skilled in the art proper method learn further and process, see for example Jackson and Hunt, (1983) " method zymetology " (Methods Enzymol.) 96:50-74.
Method of the present invention can be used following general method and program, from the initial substance that can obtain easily, prepares.Should be appreciated that when providing the typical case or preferably during processing conditions (being temperature of reaction, time, reactant molar ratio, solvent pressure etc.), unless otherwise mentioned, also can using other processing conditions.Optimum reaction condition can change with used specific reactants or solvent, but described condition can be measured by conventional optimum procedure by the those skilled in the art.
In addition, for it will be apparent to those skilled in the art that: it is essential that the GPF (General Protection False base experiences improper reaction for some functional group of prevention.Be used for the appropriate protection base of multiple functional group and known by us at technique for the protection of the conditions suitable with the deprotection particular functional group.For example; in the 2nd edition " protecting group in organic synthesis " of being shown by T.W.Greene and G.M.Wuts (Protecting Groups in Organic Synthesis) of publishing in 1991 and in the document of quoting, numerous protecting groups have been described in John Wei Li father and son publishing company (New York)
In addition, compound of the present invention contains one or more chiral centre usually.Therefore, can or be separated into pure stereoisomers by the preparation of described compound in case of necessity, i.e. independent enantiomer or diastereomer, or be the steric isomer enriched mixture.All described steric isomers (and enriched mixture) are included in category of the present invention, unless otherwise directed.Pure stereoisomers (or enriched mixture) for example can be used in this technology known optical activity initial substance or stereoselectivity reagent to prepare.Perhaps, the racemic mixture of described compound can be used for example chiral column chromatography, chirality resolving agent and similar approach thereof to separate.
Compound of the present invention is better for the preparation of convergence synthetic schemes: as illustrated in following scheme 1, make amino individuality and substituted isoquinoline acetogenin chemical combination under conventional coupling condition.
Figure BDA00002247957200491
R, R', R ", R ' ", R 1, R 2, R 3, R 4, R 5and R aas defined herein.
Pg 1refer to suitable protecting group, for example tert-butyl ester class or ortho ester class.
Scheme 1
In particular, in scheme 1, suitable 3-protection carboxyl isoquinoline (compound 1) and at least stoichiometric and better excessive amine or its N-alkyl derivative (compound 2) chemical combination of being substituted of being substituted.Under the conventional coupling condition that described reaction is known in technique, carry out.In one embodiment, reaction is under the methanol solution of sodium methylate exists, under high reaction temperature and goodly carry out under refluxing.Continue reaction until it completes substantially, this needs approximately 1 to 48 hour usually.Once reaction completes, can for example neutralize by routine techniques, extract, precipitation, chromatography, filtration and similar approach reclaim compound 3; Perhaps not purified and/or separate and for next step.
Perhaps, being substituted 3-protection carboxyl isoquinoline (compound 1) can be undertaken by the conventional peptide coupling program of knowing in technique with the coupling that is substituted amine or its N-alkyl derivative (compound 2).This coupled reaction is used the coupling reagent of knowing to carry out usually, for example carbodiimide class, bop reagent (phosphofluoric acid benzotriazole-1-base oxygen base-tri-(dimethylamino) Phosphonium) and similar reagents.The example of suitable carbodiimide class comprises dicyclohexylcarbodiimide (DCC), 1-(3-dimethylamino-propyl group)-3-ethyl carbodiimide (DECI) and similar reagents.In case of necessity, also can use the polymkeric substance carrying form of carbodiimide coupling reagent, for example comprise " tetrahedron communication " (Tetrahedron Letters), 34 (48), the reagent described in 7685 (1993).In addition, also can promote coupled reaction with the coupling promotor of knowing, for example N-hydroxy-succinamide, I-hydroxybenzotriazole and similar reagents.
Usually by by compound 1 (being generally free acid) in approximately 1 to approximately coupling reagent and at least 1 equivalent of 2 equivalents, goodly approximately 1 contact and carry out this coupled reaction in a kind of inert diluent to the about compound 2 of 1.2 equivalents, described thinner is for example methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF), DMF and similar reagents.This reaction generally between approximately 0 ℃ to approximately carrying out approximately 12 to approximately 24 hours at the temperature between 37 ℃.Once reaction completes, and by ordinary method, reclaims compound 3, described ordinary method comprises neutralization, extraction, precipitation, chromatography, filtration and similar approach.
Perhaps, can will be substituted 3-protection carboxyl isoquinoline (compound 1) thus be converted into acid halide and provide compound 3 by described acid halide and compound 2 couplings.The acid halide of compound 1 can contact to prepare with mineral acid halogenide by make compound 1 under normal condition, for example with thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, contacts or goodly contacts with oxalyl chloride.The general approximately solvent-free or mineral acid halogenide in inert solvent (for example methylene dichloride or tetracol phenixin) or the oxalyl chloride of 1 to 5 molar equivalent of using carries out this reaction, reaction between approximately 0 ℃ to approximately carrying out approximately 1 to approximately 48 hours at the temperature between 80 ℃.Also can in this reaction, use catalyzer, for example DMF.
Then by acid halide (not shown) and at least 1 equivalent, better approximately 1.1 compounds 2 to about 1.5 equivalents for example, in a kind of inert diluent (methylene dichloride), between approximately-70 ℃ to contact at the about temperature between 40 ℃ approximately 1 to approximately 24 hours.This reaction is goodly carried out under the existence of appropriate base, the acid produced for cleaning reaction.The example of appropriate base comprises tertiary amines, such as triethylamine, diisopropylethylamine, N-methyl-morpholine etc.Perhaps, reaction can be under Xiao Te-Bao Man (Schotten-Baumann) type condition comes (such as sodium hydroxide etc.) to carry out with alkaline solution.Once reaction completes, and by ordinary method, reclaims compound 3, comprises neutralization, extraction, precipitation, chromatography, filtration and similar approach.
In one embodiment, the nitrogen-atoms of isoquinoline 99.9 loop systems can be used to provide corresponding N-oxide compound (compound 4 and 5) by the routine techniques oxidation.Oxidation can be carried out with conventional oxidant under normal condition, for example metachloroperbenzoic acid or hydrogen peroxide.As narrated in scheme 1, the N-oxide compound forms and can be substituted generation on 3-protection carboxyl isoquinoline (compound 1) or compound 3.
For the initial substance of scheme 1 reaction be commercially available maybe can be by the method preparation of knowing in technique.For example glycine and N-alkyl glycine, as sarkosine, Ethylglycocoll etc. purchased from the Aldrich Chemical company (" Aldrich ") that is positioned at the Wisconsin, USA Milwaukee.
Synthesizing in technique of substituted isoquinoline acetic acid also known, and is described in detail in the United States Patent (USP) the 6th, 093,730 such as people such as Weidmann, and it is incorporated herein by reference in full.The ad hoc approach for the preparation of described derivative is set forth in following scheme 2:
Figure BDA00002247957200511
Scheme 2
In particular, in scheme 2, commercially available 4-phenyl sulfenyl-phthalonitrile (compound 6) is hydrolyzed to corresponding diprotic acid (compound 7) under normal condition, for example with the 1:1 mixture of the 50%KOH aqueous solution/methyl alcohol, processes.Continue reaction until it completes substantially, this needs approximately 48 to 96 hours usually.Once reaction completes, the diprotic acid (compound 7) that can for example neutralize by routine techniques, extract, precipitation, chromatography, filtration and similar approach reclaims gained; Perhaps not purified and/or separate and for next step.
Compound 7 cyclisation under the glycine of stoichiometric calculation equivalent exists.Reaction also then is heated to this mixture high temperature formation molten mass by the uniform mixture that at first forms reagent and carries out in solid phase.This reacts better and is heated to more than 200 ℃ and is more preferred from approximately 210 ℃ to approximately 220 ℃.Continue reaction until it completes substantially, this needs approximately 48 to 96 hours usually.Once reaction completes, the phthalic imidine (compound 8) that can for example neutralize by routine techniques, extract, precipitation, chromatography, filtration and similar approach reclaims gained; Perhaps not purified and/or separate and for next step.
The conventional esterification of compound 8 produces compound 9, wherein R 8for alkyl.This compound then stands circle amplification under alkaline condition.In particular, compound 9 is excessive with stoichiometry, and the sodium alkoxide of better 2 equivalents or alkanol potassium (for example sodium butylate) for example, contacts and maintain approximately 70 ℃ extremely approximately 120 ℃ and be preferably approximately 95 ℃ extremely approximately under the high temperature of 100 ℃ in suitable solvent (propyl carbinol).Continue reaction until it completes substantially, this needs approximately 0.5 to 6 hour usually.Once reaction completes, the isoquinoline 99.9 isomer (compound 9 and 10) that can for example neutralize by routine techniques, extract, precipitation, chromatography, filtration and similar approach reclaims gained; Perhaps not purified and/or separate and for next step.
Above-mentioned reaction conditions can cause ester functional group's transesterification (if R 8be not normal-butyl).Under any circumstance, the moieties of ester group is as the appropriate protection base of carboxyl-functional base on compound 9 and be stated as Pg in the compound 1 of scheme 1 1.
Hydroxyl-functional base on obvious 1 experiences known derivative schemes in numerous techniques.Form alkoxyl group, be substituted alkoxyl group, aryloxy, be substituted aryloxy, heteroaryloxy, be substituted heteroaryloxy, heterocyclic oxy group, be substituted heterocyclic oxy group, halogenation, dehalogenation (on this position, providing hydrogen), alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted the heteroaryl product suitable derivative comprising.On the other hand, can use the program of approving in technique to modify hydroxyl with provide-N (R 7) the R derivative, this can be by reacting the halogen substituting group to realize with suitable amine.Similarly, can prepare by ordinary method by the sulfenyl derivative of sulfenyl and oxidation, for example hydroxyl is reacted with thiophosphoric anhydride, lawesson reagent (Lawesson's reagent) or similar reagents, then optionally make the sulfhedryl of gained for example, react generation alkylthio derivative with a kind of alkylating reagent (iodic ether and similar reagents thereof).The sulfenyl derivative can be further for example, by standard peroxy acid reagent (m-chlorine peroxybenzoic acid) oxidation.
On the other hand, the replacement on the isoquinoline compound phenyl ring is reached by suitable selection initial substance.Many in described initial substance are commercially available, such as 4-phenoxy group-phthalonitrile (Aldrich) etc.Perhaps, for example can prepare by the technology of approving in technique by the compound of 4-(2,6-dimethyl phenoxy)-phthalonitrile.
Perhaps, the available commercially available compound 7 be substituted in Tetra hydro Phthalic anhydride or phthalic acid alternative scheme 1.Described acid anhydrides comprises, for example 3-difluorophthalic anhydride (Aldrich), 3-nitrophthalic acid acid anhydride (Aldrich), 3-chloro-phthalic anhydride (TCI America, Portland OR 97203 " TCI ") etc.Described acid comprises, such as 4-trifluoromethyl-phthalic acid (TCI) etc.
Test and the test of dispensing biology
The biologic activity of the compounds of this invention can be estimated by the currently known methods by any routine.Suitable analytical procedure is known by us in technique.Proposing following analysis only is not intended to limit as an example.Compound of the present invention is active in analyzing below at least one.
HIF α stability analysis based on cell
The human cell who is derived from Various Tissues is inoculation in 37 ℃, 20%O respectively in the culture dish of 35mm 2, 5%CO 2under grow up in standard culture, for example DMEM, 10%FBS.When cellular layer reaches while converging, with OPTI-MEM substratum (Invitrogen Life Technologies, Carlsbad CA), replace this substratum and cellular layer is cultivated about 24 hours under 37 ℃ in 20%O2,5%CO2.Then compound or 0.013%DMSO are added into to existing substratum and continue cultivation whole night.
After cultivation, by substratum remove, centrifugal and store with for analyzing (seeing that following VEGF and EPO analyze).Cell is cleaned in cold phosphate buffered saline (PBS) (PBS) twice and then on ice in the middle cytolysis of the 10mM of 1ml Tutofusin tris (pH7.4), 1mM EDTA, 150mM NaCl, 0.5%IGEPAL (Sigma-Aldrich, St.Louis MO) and protease inhibitor cocktail (Roche Molecular Biochemicals) 15 minutes.Cell lysates in 4 ℃ under 3,000xg centrifugal 5 minutes, and collecting cell solute segment (supernatant liquor).Suspension cell core (coccoid) cytolysis are in the 20mM HEPES of 100 μ l (pH7.2), 400mM NaCl, 1mM EDTA, 1mM dithiothreitol (DTT) and protease inhibitor cocktail (Roche Molecular Biochemicals) again, in 4 ℃ 13, under 000xg centrifugal 5 minutes, and collecting cell nucleoprotein segment (supernatant liquor).
Use QUANTIKINE immunoassay (R& D Systems, Inc., Minneapolis MN) and carry out the HIF-1 α of analysis of cells core segment according to the indication of manufacturer.
VEGF based on cell and the elisa assay of EPO
Use applicable QUANTIKINE immunoassay (R& D Systems, Inc., Minneapolis MN) and according to the indication of manufacturer analyze and collect from the vascular endothelial growth factor (VEGF) through regulating substratum of above-mentioned cell cultures and/or the expression of erythropoietin (EPO).
Oxygen consumption is analyzed
Oxygen sensor Tissue Culture Plate (BD Biosciences) contains have more epipolic ruthenium complex when anoxic.Therefore, while having the oxygen consumption cell in plate, it changes into lower oxygen saturation and the fluorescence of Geng Gao by balance, thereby increase fluorescence, reads.We estimate: the compound of stablizing HIF by suppressing hydroxylation can reduce oxygen consumption to the consumption of oxygen and/or by cellular metabolism is changed to the anaerobism production capacity by aerobic production capacity by reducing hydroxylation self.
At 37 ℃, 10%CO 2under make to be derived from fetal kidney epithelium (293A) or uterine cervix epithelium gland cancer (HeLa) (the American Type Culture Collection that adenovirus transforms, Manassas VA) human cell is at substratum (high glucose DMEM (Mediatech, Inc., Herndon VA), 1% penicillin (penicillin)/Streptomycin sulphate (streptomycin) mixture (Mediatech), 1% fetal bovine serum) in grow to and converge.Collecting cell and in substratum the density with 500,000 cells/ml suspend again.By cell suspending liquid with the 0.2ml/ pore distribution in each hole of oxygen biosensor 96 porocyte culture plates (BD Biosciences, Bedford MA).The following handled thing of 10 μ l volumes is added in three groups of holes: (1) 0.5%DMSO; (2) 200 μ M sodium lauryl sulphate; Or (3) 1,10 or 50 μ M compound.
In 37 ℃, 10%CO 2lower cultivation culture 72 hours then in FL600 fluorometer (Biotek Instruments, Inc., Winooski VT) reads culture plate under the emission wavelength of the excitation wavelength of 485nm and 590nm.Control (O with the function that folds change with respect to DMSO 2consume) or the specific absorption under the 450nm wavelength (WST-1) is mapped data and use EXCEL software (Microsoft Corporation, Bellevue WA) to be described statistical analysis.
HIF-PH2 (PHD2) analyzes
Material
HIF-PH2 (EGLN1) is from the Hi5 cell expressing and by SP ion-exchange chromatography partial purification.Ketoisocaproic-[1-14C]-sodium salt derives from Perkin-Elmer.The alpha Ketoglutarate sodium salt is purchased from SIGMA.DLD19 peptide (ethanoyl-DLDLEMLAPYIPMDDDFQL-CONH that the HPLC purifying is crossed 2) by Synpep, made.
HIF-PH2 (EGLN2) is from insect Hi5 cell expressing and by SP ion-exchange chromatography partial purification.By using the analysis of being described by Kivirikko and Myllyla (1982, " method zymetology " (Methods Enzymol) 82:245-304), catch 14cO 2measure enzymic activity.Analytical reaction contain 50mM HEPES (pH7.4), 100 μ M α-ketoglutaric acid sodium salts, 0.30 μ Ci/ml ketoisocaproic μ-[1- 14c]-sodium salt (Perkin Elmer, Wellesley MA), 40 μ M FeSO 4, 1mM ascorbate salt, 1541.8 units/ml catalase, there are or do not have 50 μ M peptide matrix (ethanoyl DLDLEMLAPYIPMDDDFQL-CONH 2) and the compound of the present invention of different concns.Reaction starts by adding the HIF-PH2 enzyme.
Conversion percentage ratio while by deducting the conversion percentage ratio when having the matrix peptide, lacking peptide calculates peptide dependency conversion percentage ratio.Use the peptide dependency conversion percentage ratio under given inhibitor concentration to calculate inhibition percentage ratio and IC 50.Use GraFit software (Erithacus Software Ltd., Surrey UK) to calculate the IC of each inhibitor 50value.
Medicine formula and dosing way
Composition of the present invention can directly be carried or carry in medical composition together with suitable supporting agent or the vehicle known in technique.Existing methods for the treatment of can comprise offers medicine the compounds of this invention of significant quantity to the experimenter who dialyses or perform the operation and suffer from anaemia or anaemia danger is arranged due to for example chronic renal failure, diabetes, cancer, AIDS, radiotherapy, chemotherapy, kidney.In a preferred embodiment, the experimenter is mammalian subject, and, in the embodiment an of the best, the experimenter is the human experimenter.
The significant quantity of described medicament can be measured easily by normal experiment, equally the most effectively with the most convenient dosing way and the most applicable formula, also can measure easily by normal experiment.Can utilize multiple formulations and delivery system in technique.See for example above-mentioned Gennaro, the nineteen ninety-five that A.R. edits publishes " Lei Shi pharmacy complete works ".
Suitable dosing way can comprise, for example oral, per rectum, in mucous membrane, nose or intestines dispensing and parenteral delivery, comprise in intramuscular, subcutaneous, intramedullary injection and intrathoracic, direct ventricle, in intravenously, intraperitoneal, nose or intraocular injection.Medicament or its composition can be with part but not the mode of whole body cast.For example, a kind of suitable medicament can or be carried via injection in a kind of targeted drug delivery system, and described targeted drug delivery system is for example long-acting or sustained release formula.
Medical composition of the present invention can be thus in a technology known any method manufacture, for example by conventional mixing, dissolving, granulation, dressing, pulverizing, emulsification, inclosure capsule, seal or freeze drying process.As mentioned above, composition of the present invention can comprise the acceptable supporting agent of one or more physiology, for example is convenient to bioactive molecule is machined to vehicle and the auxiliary agent in the preparation of medicinal use.
Suitable formula depends on selected dosing way.For example, for injection, can in the aqueous solution, allocate described composition, allocate in the better damping fluid compatible at physiology, for example hanks' solution (Hanks'solution), ringer's solution (Ringer's solution) or normal saline buffer solution.For through mucous membrane or nose dispensing, will be suitable for the permeate agent of permeability barrier for formula.Described permeate agent is generally known in technique.In a preferred embodiment of the present invention, prepared by compound of the present invention in the formula in order to oral.For oral, can combine by the pharmaceutically acceptable supporting agent by knowing in active compound and technique and allocate easily described compound.Described supporting agent can be allocated as compound of the present invention tablet for experimenter's orally ingestible, pill, drageeing, capsule, liquid, gel, syrup, ointment, suspension etc.Described compound is also adjustable is rectal compositions, for example contains suppository or the enema,retention of conventional suppository base (for example theobroma oil or other glyceride type).
As solid excipients, after adding suitable auxiliary agents where necessary, optionally grind the mixture of gained processing granular mixture to obtain the core of tablet or drageeing, can obtain the pharmaceutical preparation for orally using.Suitable vehicle is in particular weighting agent, and for example sugar, comprise lactose, sucrose, N.F,USP MANNITOL or Sorbitol Powder; Cellulose preparation, for example W-Gum, wheat starch, rice fecula, potato starch, gelatin, tragacanth gum, methylcellulose gum, Vltra tears, Xylo-Mucine and/or polyvinylpyrrolidone (PVP).Can add disintegrating agent in case of necessity, for example cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, for example sodium alginate.Also comprise wetting agent, for example sodium lauryl sulphate.
The drageeing core has suitable dressing.Can use concentrated sugar soln, it optionally contains Sudan Gum-arabic, talcum, polyvinylpyrrolidone, carbopol gel, polyoxyethylene glycol and/or titanium dioxide, paint solution and suitable organic solvent or solvent mixture for this reason.Dyestuff or pigment can be added into tablet or drageeing dressing, in order to the various combination of identification or characterization active compound doses.
Comprise for oral pharmaceutical preparation the push style capsule made by gelatin, and the soft seal capsule for example, made by gelatin and softening agent (glycerine or Sorbitol Powder).The push style capsule can contain the activeconstituents for example, for example, for example, mixed with weighting agent (lactose), tackiness agent (starch) and/or lubricant (talcum or Magnesium Stearate) and the stablizer optionally added.In soft capsule, active compound solubilized or be suspended in suitable liquid, for example fatty oil, whiteruss or liquid macrogol.In addition, can add stablizer.The dosage of all formula of oral should be suitable for described dispensing.
In one embodiment, compound of the present invention can give (for example pasting by skin) or part gives through skin.In one aspect, of the present inventionly through skin or local prescription, can comprise in addition one or more penetration enhancers or other effector, comprise and strengthen the medicament that institute's compound of carrying moves.For example, in the situation that needs are located conveying, preferably through skin or topical administration.
For inhalation dosing, according to compound used in the present invention, can use suitable propelling agent form with aerosol spray from pressurized package or atomizer to carry expediently, described propelling agent is dichloro two fluoro methane, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or any other suitable gas for example.In the situation that pressurised aerosol, applicable dose unit can be determined with the amount of conveying and metering by a valve is provided.Capsule and the cartridge case of the adjustable for example gelatin used in sucker or insufflator.These capsules and cartridge case contain the powdered mixture of compound and suitable powder matrix, for example lactose or starch usually.
Through allotment, with for by injection, for example by bolus injection or continuous infusion, come the composition of parenteral admistration can unit dosage form to exist, for example be present in ampoule together with the sanitas added or in multi-dose container.Described composition can be taked the form as the emulsion in suspension, solution or oil or hydrophily agent, and can contain for example blender of suspension agent, stablizer and/or dispersion agent.The composition that comprises the aqueous solution or other water-soluble form for the formula of parenteral admistration.
The suspension of active compound also can be prepared as suitable oily injection suspensions.Suitable lipophilic solvent or mediator comprise fatty oils, for example sesame oil and Acrawax class, for example ethyl oleate or tri-glyceride or liposome class.Water injection suspension liquid can contain the material that increases suspension viscosity, for example Xylo-Mucine, Sorbitol Powder or dextran.Described suspension optionally also can contain suitable stablizer or increase the reagent solution highly concentrated in order to preparation of compound dissolution degree.Perhaps, activeconstituents can be powder type, in order to before use with suitable mediator, for example sterile pyrogen-free water combination.
As mentioned above, also compound of the present invention can be allocated as to prolonged action preparation.The formula of described long term can for example, by implanting (subcutaneous or intramuscular) or casting by intramuscularly.For example, for example, thereby for example compound of the present invention can be allocated together with suitable polymerization or lyophobic dust (being emulsion form in can accepting oil) or ion exchange resin, or is allocated as the slightly soluble derivative, slightly soluble salt.
Suitable supporting agent for hydrophobic molecule of the present invention is known by us at technique and is comprised the cosolvent system, and it comprises for example phenylcarbinol, a kind of non-polar surfactant, a kind of organic polymer and water that can be miscible with water.The cosolvent system can be VPD cosolvent system.VPD is the solution of 3%w/v phenylcarbinol, 8%w/v non-polar surfactant polysorbate 80 and 65%w/v Liquid Macrogol constant volume in dehydrated alcohol.VPD cosolvent system (VPD:5W) is comprised of the VPD of 5% D/W 1:1 dilution.This cosolvent system is solubilizing hydrophobic compound produce hypotoxicity when the whole body administration effectively.The ratio of cosolvent system naturally can greatly change and not destroy its solubleness and toxic characteristic.In addition, cosolvent component itself can change.For example, can replace polysorbate 80 with other hypotoxicity non-polar surfactant; The clip size of polyoxyethylene glycol can change; Other bioavailable polymer can replace polyoxyethylene glycol, for example polyvinylpyrrolidone; And other carbohydrate or polyose can replace glucose.
Perhaps, can use other delivery system for hydrophobic molecule.Liposome and emulsion are the examples of knowing for the conveying mediator of hydrophobic drug or supporting agent.In the above content about gene delivery system, the liposome delivery system has been discussed.Although the toxicity that Chang Yigeng is large is cost, also can use some organic solvent, for example methyl-sulphoxide.In addition, can carry described compound by sustained release system, for example contain the semi-permeable matrix of the solid hydrophobic polymkeric substance of significant quantity composition to be cast.Determined multiple sustained-release material and can be the those skilled in the art and utilized.Depend on its chemical property, the sustained release capsule can discharge several Zhou Zhizhi of compound more than 100 days.The chemical property and the biological stability that depend on therapeutical agent, can be used other strategy for protein stability.
For any composition for this methods for the treatment of, can use at first the technology of knowing in multiple technique to estimate the treatment effective dose.For example, in cell culture assays, can in animal model, design dosage to reach the circulation composition scope, it is included in the IC measured in cell cultures 50.The dosage range that is suitable for the human experimenter can for example use the data that obtain from cell cultures and other zooscopy to determine.
A kind for the treatment of effective dose of medicament instructs the pharmaceutical quantities that causes doing well,improving or experimenter's prolonged survival period.The toxicity of described molecule and treatment effect can be measured by standard medicine program in cell cultures or in laboratory animal, for example, by measuring LD 50(overall 50% lethal dose) and ED 50(overall 50% treatment effective dose).Toxic effect is therapeutic index to the dose ratio of result for the treatment of, and it can be expressed as LD 50/ ED 50ratio.Preferably show the reagent of high therapeutic index.
Dosage is better for comprising ED 50and have seldom in toxicity or avirulent circulation composition scope.Depend on used dosage form and the dosing way utilized, dosage can change in this scope.Consider the details of experimenter's patient's condition, should select definite formula, dosing way and dosage according to method known in technique.
Can adjust individually dosage and interval in order to the plasma content be enough to by the active part of required adjusting endogenous erythropoietin plasma content to be provided, i.e. minimum effective concentration (MEC).For each compound, MEC can change but can estimate from for example vitro data.Reach the necessary dosage of MEC and depend on personal feature and dosing way.Medicament or its composition should cast with in treatment time length of the treatment time length at about 10-90%, better about 30-90% and the treatment time length between best 50-90%, maintaining the scheme of plasma content more than MEC.In the situation that topical administration or selectivity absorb, effective partial concn of medicine may be irrelevant with plasma concentration.Perhaps, the stimulation of endogenous erythropoietin can reach by following steps: 1) cast loading dose, then cast maintenance dose, 2) cast inductive dose to reach rapidly erythropoietin content in target zone, then cast lower maintenance dose in required target zone, to maintain hematocrit, or 3) administration of repetition discontinuity.
Certainly, the medicament cast or the amount of composition depend on many factors, comprise the experimenter's who is treating sex, age and body weight, painful seriousness, dosing mode and prescriber's judgement.
In case of necessity, composition of the present invention can be present in the packing or dispenser device of the one or more unit dosage forms that contain activeconstituents.For example, described packing or equipment can comprise metal or plastic foil, for example Blister Package.Described packing or dispenser device can be with the dispensing indications.Also can prepare and comprise the composition of allocating the compounds of this invention in compatible medical carrier, be placed in suitable container also labelled in order to treat the indicated patient's condition.On label, the indicated suitable patient's condition can comprise the treatment of the patient's condition, illness or disease that anaemia is main sign.
In view of the disclosure of this paper, these and other embodiment of the present invention will easily understand and be to expect especially the those skilled in the art.
Example
Can further understand the present invention by reference to following instance, described example is purely in order to the present invention that demonstrates.The present invention is not restricted in the category of example embodiment, and it is only in order to the explanation as to single aspect of the present invention.The method of any equivalence on function is all in category of the present invention.Except modification described herein, description and accompanying drawing multiple modification of the present invention by before will become apparent for the those skilled in the art.In the described category that is modified in additional claims.
Unless otherwise mentioned, otherwise all temperature be degree centigrade.And, neutralize other local abbreviation occurred at these examples and there is following implication:
μ l=microlitre
Amu=atomic mass unit
Atm=normal atmosphere
Bs=wide unimodal
ClCO 2iBu=isobutyl chlorocarbonate
ClCONMe 2=dimethylamino formyl chloride
Conc.=concentrated
D=doublet
DABCO=diazabicyclo [2.2.2] octane
Dd=double doublet
DMF=dimethyl formamide
DMSO=methyl-sulphoxide
Et 2sO 4=sulfovinic acid
EtI=iodic ether
EtOAc=ethyl acetate
EtOH=ethanol
EtOH=ethanol
G=gram
H=hour
HATU=phosphofluoric acid N-dimethylamino
-1H-1,2,3-triazolo [4,5-b] pyridine
-1-methylene-N-methyl first ammonium N-
Oxide compound
HBTU=1-H-benzotriazole salt
Hz=hertz
M=mole
M=multiplet
Me 2sO 4=methyl-sulfate
Me 3oBF 4=trimethylboroxin
MeI=methyl iodide
MeOCH 2i=iodine methoxyl group methane
MeOH=methyl alcohol
MeONa=sodium methylate
Mg=milligram
MHz=megahertz
Min=minute
Ml=milliliter
Mmol=mmole
N=equivalent concentration
NaOMe=sodium methylate
N-BuLi=n-Butyl Lithium
N-BuOH=propyl carbinol
NEt 3=triethylamine
PhCH 2br=toluene bromide
Q=quartet
Quint=quintet
R.t.=room temperature
R f=retention factors
S=second
T=triplet
TFA=trifluoroacetic acid
THF=tetrahydrofuran (THF)
TLC=tlc
Wt%=weight percent
Example A-1
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Under room temperature at 15ml CH 2cl 2benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (can be according to the people's such as Weidmann United States Patent (USP) 6 for middle stirring 0.33g6-, 093,730,10/1998 acquisition), 0.5ml triethylamine, 0.38g HATU and the commercially available ALANINE methyl ester hydrochloride of 0.151g 18h, produce afterwards (S)-2-[(6-benzyloxy of the solid that is white in color-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl at silica gel chromatography (elutriant=4:1 hexane-EtOAc))-amino]-methyl propionate 0.220g, MS-(+)-ion, M+1=415.8amu.
B. (S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
At room temperature stir 0.200g example A-1a) described in (S) methyl esters and 15ml 1.5M NaOH methanol solution 3h concentrated.Resistates is dissolved in the water and extracts with EtOAc.With hydrochloric acid, water layer is acidified to the pH value and is about 1 and collect the throw out of gained by filtration, water cleans, dryly in vacuum drying oven (70 ℃) with generation, be the 0.174g (S) of creamy white-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid, MS-(+)-ion, M+1=401.0amu.
Example A-2
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
A. (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-butylacetate
The mixture of 160ml butanols, 20.0g (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetic acid (94.6mmol) and the 2.0ml vitriol oil 24h that under agitation refluxes.Then by part adding a 5g sodium bicarbonate, continue at room temperature to stir 5min evaporating solvent in a vacuum.Resistates is divided in 100ml water and 100ml ethyl acetate molten.Clean organic phase with 100ml salt solution, via dried over sodium sulfate, also evaporate in a vacuum to produce the micro-yellow oil with after coagulation.Obtain the 24.02g title compound; MS-(+)-ion:
B.1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation 4.41g sodium (190mmol) is dissolved in the 250ml propyl carbinol.After sodium dissolves fully, make solution be cooled to envrionment temperature and under agitation add 24.0g (91.9mmol) (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-butylacetate and be dissolved in the solution of 150ml butanols.This solution is heated to 100 ℃ and stir 1h at this temperature in 30min.Then make this mixture be cooled to envrionment temperature and store at ambient temperature 18h.Then by under agitation adding the 2N aqueous hydrochloric acid, the pH value of mixture is adjusted into to 2 to 3.Continue to stir 30min, then suction filtration solid ingredient.Water thoroughly clean filter cake and under vacuum in 50 ℃ of dryings to produce white solid.Obtain the 17.75g title compound; MS-(+)-ion:
C.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Stir at ambient temperature the mixture 1h of 17.3g (66.2mmol) Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester and 100ml phosphorus oxychloride and then under agitation in 2h, slowly be heated to reflux temperature.This mixture of gentle reflux 30min under agitation.After being cooled to room temperature, evaporating in a vacuum excessive phosphorus oxychloride and resistates is dissolved in the 100ml ethyl acetate.This solution is under agitation injected to the 300ml saturated sodium bicarbonate aqueous solution.Formed throw out removes by vacuum filtration.Separate organic phase and by the ethyl acetate aqueous phase extracted of 3 * 100ml.Merge water via dried over sodium sulfate, by silicagel pad, filter and also evaporate in a vacuum to produce the brown oil with after coagulation.Obtain the 11.37g title compound; 1h NMR (CDC1 3): δ=11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
D.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid
The mixture 2h of 9.23g1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (33mmol), 90ml2.5N aqueous sodium hydroxide solution, water (20ml) and the ethanol (110ml) of under agitation refluxing.Then by adding concentrated hydrochloric acid aqueous solution, the pH value of mixture is adjusted into to 2.In adding procedure, by by the cooling temperature of mixture that makes of ice bath, remaining on 20 ℃.Then continue to stir 1h, then by the isolated by vacuum filtration solid ingredient.Water clean filter cake and under vacuum in 85 ℃ of dryings to produce white powder.Obtain the 6.64g title compound; MS-(+)-ion: M+1=224.1amu.
E. (R)-3-tert.-butoxy-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-the propionic acid tert-butyl ester
122.5 μ l (0.7mmol) ethyl-di-isopropyls-amine under agitation is added in the mixture of 45mg (0.2mmol) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid, 76mg (0.2mmol) phosphofluoric acid benzotriazole-1-base-(two-dimethylamino-methylene radical)-oxygen (HBTU), 50.8mg (R)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride (0.2mmol) and 1ml methylene dichloride.Continue at ambient temperature to stir 40h.Use hexane: ethyl acetate (9:1) is as elutriant, by flash column chromatography on silica gel from reaction mixture separated product to produce water white oil.Obtain the 27mg title compound; MS-(+)-ion: M+1=422.8amu.
F. (R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Stir at ambient temperature 27mg (0.06mmol) (R)-3-tert.-butoxy-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-the mixture 2h of the propionic acid tert-butyl ester and 2ml trifluoroacetic acid.Then evaporate in a vacuum excessive trifluoroacetic acid, be dissolved in the 2ml dehydrated alcohol by resistates and concentrate in a vacuum this solution to produce the brown color solid.Obtain the 27mg title compound; MS-(+)-ion: M+1=310.9amu.
Example A-3
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to example A-2e) and f), by from example A-2d) l-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and (S)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepare; MS-(+)-ion: M+1=310.9amu.
Example A-4
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to example A-2e) and f), (can be according to the people's such as Weidmann United States Patent (USP) 6 by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid, 093,730,10/1998 obtains) and (R)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepare; MS-(+)-ion: M+1=369.0amu.
Example A-5
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to example A-2e) and f), (can be according to the people's such as Weidmann United States Patent (USP) 6 by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid, 093,730,10/1998 obtains) and (S)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepare; MS-(+)-ion: M+1=369.0amu.
Example A-6
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to example A-2e) and f), (can be according to the people's such as Weidmann United States Patent (USP) 6 by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid, 093,730,10/1998 obtains) and (R)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepare; MS-(+)-ion: M+1=369.0amu.
Example A-7
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to example A-2e) and f), (can be according to the people's such as Weidmann United States Patent (USP) 6 by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid, 093,730,10/1998 obtains) and (S)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepare; MS-(+)-ion: M+1=369.0amu.
Example A-8
2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid
Be similar to example A-1a) and b), by from example A-2d) l-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and 2-amino-2-methyl-methyl propionate hydrochloride prepare; MS-(+)-ion: M+1=308.9amu.
Example A-9
2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid
Be similar to example A-1a) and b), by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (can obtain according to the people's such as Weidmann United States Patent (USP) 6,093,730,10/1998) and 2-amino-2-methyl-methyl propionate hydrochloride, prepared; MS-(+)-ion: M+1=367.0amu.
Example A-10
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(lH-imidazol-4 yl)-propionic acid; Three fluoro-acetates
Be similar to example A-2e), by from example A-2d) l-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and (R)-2-amino-3-(1-trityl-lH-imidazol-4 yl)-methyl propionate hydrochloride start, then be similar to example A-1b) deprotection and then be similar to 2f) prepare; MS-(+)-ion: M-1=359.1amu.
Example A-11
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(lH-imidazol-4 yl)-propionic acid; Three fluoro-acetates
Be similar to example A-2e), by from example A-2d) l-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and (S)-2-amino-3-(1-trityl-lH-imidazol-4 yl)-methyl propionate hydrochloride start, then be similar to example A-1b) deprotection and then be similar to 2f) prepare; MS-(+)-ion: M-1=359.1amu.
Example A-12
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to example A-1a) and b) prepare; MS-(-)-ion: M-1=321.1amu.
Example A-13
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=323.0amu.
Example A-14
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=381.1amu.
Example A-15
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=381.0amu.
Example A-16
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=381.0amu.
Example A-17
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=381.0amu.
Example A-18
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to example A-1a) and b) prepare; MS-(-)-ion: M-1=429.0amu.
Example A-19
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=371.0amu.
Example A-20
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Being similar to example A-2e} and f} prepares; MS-(+)-ion: M+1=371.0amu.
Example A-21
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=429.0amu.
Example A-22
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=429.0amu.
Example A-23
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=429.0amu.
Example A-24
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=429.0amu.
Example A-25
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M-1=385.0amu.
Example A-26
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=387.1amu.
Example A-27
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Being similar to example A-2e} and f} prepares; MS-(-)-ion: M-1=443.0amu.
Example A-28
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Being similar to example A-2e} and f} prepares; MS-(-)-ion: M-1=443.0amu.
Example A-29
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=445.1amu.
Example A-30
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=445.1amu.
Example A-31
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid
Be similar to example A-1a) and b) prepare; MS-(+)-ion: M+1=381.0amu.
Example A-32
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid
Be similar to example A-1a) and b) prepare; MS-(-)-ion: M-1=379.0amu.
Example A-33
(R)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=321.0amu.
Example A-34
(S)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=321.0amu.
Example A-35
(R)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=379.1amu.
Example A-36
(S)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=379.1amu.
Example A-37
(R)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=352.2amu.
Example A-38
(S)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=352.1amu.
Example A-39
(R)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=410.1amu.
Example A-40
(S)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=410.1amu.
Example A-41
(R)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=410.1amu.
Example A-42
(S)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=410.1amu.
Example A-43
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to example A-1a) and b) prepare; MS-(+)-ion: M+1=338.9amu.
Example A-44
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to example A-2e) and f) prepare; MS-(-)-ion: M-1=337.0amu.
Example A-45
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to example A-1a) and b) prepare; MS-(+)-ion: M+1=397.0amu.
Example A-46
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to example A-2e) and f) prepare; MS-(+)-ion: M+1=397.1amu.
Example A-47
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to example A-1a) and b) prepare; MS-(+)-ion: M+1=397.0amu.
Example A-48
1-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropane-carboxylic acid
Be similar to example A-1a) and b) prepare; MS-(-)-ion: M-1=305.0amu.
Example A-49
1-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropane-carboxylic acid
Be similar to example A-1a) and b) prepare; MS-(+)-ion: M+1=365.0amu.
Example A-50
Two deuteriums-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Under agitation by 70mg (0.25mmol) from example A-2c) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester, 193mg (2.5mmol) glycine-2,2-d 2mixture backflow 15h with the methanol solution of sodium methylate of 5ml0.5N.Follow evaporating solvent in a vacuum, resistates is dissolved in 8ml water and cleans this solution by the ethyl acetate of 2 * 20ml.By interpolation 1N aqueous hydrochloric acid, the pH value of this solution is adjusted into to 3 and also by the ethyl acetate of 3 * 20ml, extracts this mixture.Via dried over mgso, this merges extract concentrated to produce white solid in a vacuum.Obtain the 61mg title compound; MS-(-)-ion: M-1=280.9amu.
Example A-51
(R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Be similar to example A-1a), make 0.33g6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the coupling of 0.150g D-alanine methyl ester hydrochloride.Obtain 0.205g creamy white solid product, MS-(+)-ion, M+1=415.0amu.
B. (R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-1b) prepare 0.164g white solid: MS-(=)-ion, M+1=401.1amu.
Example A-52
(S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Be similar to example A-1a), make 0.33g7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the coupling of 0.150g ALANINE methyl ester hydrochloride.Obtain the 0.264g white solid: MS-(+)-ion, M+1=415.amu.
B. (S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-1b) prepare 0.216g white solid: MS-(+)-ion, M+1=401.9amu.
Example A-53
(R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Be similar to example A-1a), make 0.33g7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the coupling of D-alanine methyl esters.Obtain 0.246g creamy white solid: MS-(+)-ion, M+1=415.0amu.
B. (R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-1b) prepare 0.211g creamy white solid: MS-(+)-ion, M+1=401.0amu.
Example A-54
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) (S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Stir 0.55g1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid, 1.5ml triethylamine, 0.55g DECI and 0.56g (L)-alanine methyl ester hydrochloride 72h in the 15ml methylene dichloride under room temperature.Reaction mixture is divided between ethyl acetate and water molten, separate organic layer also successively with the 1M HCl aqueous solution, saturated NaHCO 3the aqueous solution and saturated NaCl aqueous cleaning.With dried over sodium sulfate organic layer, filtration concentrated so that 0.133g creamy white solid product to be provided under vacuum.MS-(+)-ion, M+1=308.9 dalton.
B) (S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-1b), by example A-54a) described in the saponification/acidifying of 0.116g (S) methyl esters, produce the 0.087g white solid product: MS-(+)-ion, M+1=294.9amu.
Example A-55
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Be similar to example A-54a), make 0.55g1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the methyl esters coupling of 0.40g D-alanine and obtain 0.200g creamy white solid product: MS-(+)-ion, M+1=308.8amu.
B. (R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-1b) prepare 0.127g white solid: MS-(+)-ion, M+1=294.9amu.
Example A-56
(S)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-1a) condition under, 0.030g6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and 0.046g HATU are reacted with 0.017g ALANINE methyl esters.At room temperature with 0.014g NaOH, in the 0.1ml1:1 methanol-water, process crude product 2 days, then by 1M hcl acidifying to pH value, be about 2.Collect product by filtration, water cleans and is dry to produce 0.023g creamy white solid: MS-(-)-ion, M-1=353.0amu.
Example A-57
(R)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-56, make 0.030g6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the coupling of D-alanine methyl ester hydrochloride and be hydrolyzed this product to produce 0.022g creamy white solid: MS-(-)-ion, M-1=353.0amu.
Example A-58
(S)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-56, make 0.040g7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the reaction of 0.020g ALANINE methyl ester hydrochloride, will produce the 0.047g white solid after middle ester hydrolysis: MS-(-)-ion, M-1=353.1amu.
Example A-59
(R)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-56, make 0.040g7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the reaction of D-alanine methyl ester hydrochloride.As in example A-56, middle ester products is hydrolyzed to produce 0.042g white solid: MS-(-)-ion, M-1=353.0amu.
Example A-60
2-(S)-{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 4-(the chloro-phenoxy group of 4-)-phthalonitrile
Make mixture backflow 3h in acetone (87ml) of 4-nitrophthalonitrile (5.0g), 4-chlorophenol (3.13ml) and salt of wormwood (7.99g).After filtering and concentrating, resistates is dissolved in ethyl acetate (100ml).Clean this solution with NaOH (1N, 50ml * 3) and salt solution.Dry organic layer, filtration, concentrated and dilute with methylene dichloride.Filter and rinse by silicagel pad, produce the 5.7g title compound. 1H NMR(200MHz,DMSO)δ8.09(d,J=9Hz,1H),7.83(d,J=2.6,1H),7.53(d,J=8.6Hz,2H),7.42(dd,J=2.8,8.6Hz,1H),7.24(d,J=8.6,2H)。
B) 4-(the chloro-phenoxy group of 4-)-phthalic acid
Mixture backflow 18h by 1.31g4-(the chloro-phenoxy group of 4-)-phthalonitrile, 45% potassium hydroxide (3.5ml) and methyl alcohol (3.5ml).Add 6N HCl the pH value is adjusted to 4.Filtering precipitate, water clean and are dry to produce the 1.45g title compound.MS-(-)-ion: M-1=291.0amu.
C) [5-(the chloro-phenoxy group of 4-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
The mixture of 500mg4-(the chloro-phenoxy group of 4-)-phthalic acid and the positive butyl ester of glycine (286mg) is heated to 5min under 250 ℃.By chromatography, using methylene dichloride as elutriant by the reaction mixture purifying to produce the title compound of 436mg. 1H NMR(200MHz,DMSO)δ7.48(d,J=8.6Hz,1H),7.59(d,J=9.0Hz,2H),7.46(m,2H),7.29(d,J=9.0Hz,2H),4.46(s,2H),4.16(t,J=6.2Hz,2H),1.61(m,2H),1.38(m,2H),0.92(t,J=7.0Hz,3H)。
D) 6-and 7-(the chloro-phenoxy group of 4-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-2b) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=386.1.
E) the chloro-6-of 1-and 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-2c) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=404.2.
F) 6-and 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester:
Mixture backflow 25min by the chloro-6-of l-and 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (280mg), 0.27ml57 % by weight HI, Glacial acetic acid (3ml) and red phosphorus (43mg).Then this mixture of dilute with water, use solid NaHCO 3alkalize to the pH value be 8, be extracted with ethyl acetate (2 times).Clean ethyl acetate layer with sodium metabisulfite solution, saturated sodium bicarbonate, dry and concentrated.Use hexane/ethyl acetate, by chromatography purification to produce 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (103mg, the compound of example A-60a): MS-(-)-ion: M-1=370.3 and 6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (71mg, the compound of example 60b): MS-(-)-ion: M-1=370.3.
G) 2-(S)-{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to example A-50, by prepared in 130 ℃ of reaction 20min by 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of example A-60a) and ALANINE in microwave reactor.MS-(-)-ion: M-1=385.1.
Example A-61
2-(S)-{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to example A-50, by prepared in 130 ℃ of reaction 25min by 6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of example A-60b) and ALANINE in microwave reactor.MS-(-)-ion: M-1=385.1.
Example A-62
2-{[7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 5-(the fluoro-phenoxy group of 3,4-bis-)-isoindole-1, the 3-diketone
By 3,4-difluorophenol (650mg) and benzene azeotropic and be dissolved in the methanol solution of sodium methylate (0.5M, 10ml).Then under nitrogen, decompression removes methyl alcohol.In mixture before then dry DMF (10ml) solution of 4-nitro phthalic imidine (769mg) being added into.The mixture of gained is at refluxed under nitrogen 23h.Cooling and the interpolation 80ml water by reaction.Filter the throw out of gained, water cleans (4 times) the dry title compound with generation 685mg.MS-(-)-ion: M-1=274.3.
B) [5-(the fluoro-phenoxy group of 3,4-bis-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
By 5-(the fluoro-phenoxy group of 3,4-bis-)-isoindole-1,3-diketone (680mg), salt of wormwood (1g), propione (20ml) and methyl bromoacetate (295 μ L) are added into penstock.The mixture of gained is heated to 105 ℃, continues 17h.With 20ml water diluting reaction thing and be extracted with ethyl acetate (2 times).Dry organic layer is also concentrated.By silica gel chromatography, use 4:1 hexane/ethyl acetate and 3:1 hexane/ethyl acetate purified mixture to produce the 657mg title compound. 1H NMR(200MHz,DMSO)δ7.95(d,J=9.0Hz,1H),7.64-7.41(m,4H),7.15-7.08(m,1H),4.44(s,2H),3.70(s,3H)。
C) 6-and 7-(the fluoro-phenoxy group of 3,4-bis-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-2b) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=388.1.
D) the chloro-6-of 1-and 7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-2c) prepare.The mixture of two kinds of isomer directly continues on for next step.
E) 6-and 7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
By 10%Pd/C, (50% is wet, 88mg) is added in ethyl acetate (4ml) solution of the chloro-6-of l-and 7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (220mg) and then adds ammonium formiate (340mg).The mixture of gained is heated to reflux, continues 0.5h.After cooling, use the ethyl acetate diluted reaction mixture and filter by Celite pad.Concentrating filtrate also separates to produce 131mg7-(3 by chromatography, the fluoro-phenoxy group of 4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of example A-62a) and 55mg6-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of example A-62b).
F) 2-{[7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to example A-50, by prepared over 3 days in 85 ℃ of reactions by 7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of example A-62a) and ALANINE in penstock.MS-(+)-ion: M-1=389.2.
Example A-63
2-(S)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 4-phenyl sulfenyl-phthalic acid
5.06g4-phenyl sulfenyl-phthalonitrile (21.4mmol), the 10ml50%KOH aqueous solution and 10ml methyl alcohol 3.5 days under agitation reflux.Then with this mixture of dilution of 100ml water, also use the concentrated hydrochloric acid acidifying.The suction filtration precipitated product, water thoroughly cleans also in a vacuum in 60 ℃ of dryings.Obtain the 5.75g title compound; MS-(-)-ion: M-1=273.0.
B) (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-acetic acid
In mortar, 5.62g4-phenyl sulfenyl-phthalic acid (20.5mmol) and 1.55g glycine (20.5mmol) are thoroughly ground together.Then in oil bath, this mixture is heated to 210 ℃ to 220 ℃.Stir molten mass 15min with scraper at this temperature, then it is cooled to envrionment temperature in a vacuum.Obtain the 6.30g title compound; MS-(-)-ion: M-1=311.8; 1h NMR (DMSO-d 6): δ=7.82 (d, 1H), 7.46-7.62 (m, 7H), 4.26 (s, 2H).
C) (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
Under agitation by the mixture backflow 18h of 20ml methyl alcohol, 6.27g (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-acetic acid (20mmol) and the 0.3ml vitriol oil.Then add the dense sodium bicarbonate aqueous solution of 100ml and extract this mixture by the 100ml ethyl acetate.Via MgSO 4dry organic phase evaporation in a vacuum.Obtain the 6.30g title compound; MS-(+)-ion: M+1=328.0; 1h NMR (CDC1 3): δ=7.69 (d, 1H), 7.41-7.55 (m, 7H), 4.40 (s, 2H), 3.75 (s, 3H).
D) Isosorbide-5-Nitrae-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (B)
Under agitation 0.92g sodium (40mmol) is dissolved in the 100ml propyl carbinol.Then temperature is increased to 95 ℃ to 100 ℃, add 6.5g (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate (19.85mmol) is dissolved in the hot solution in the 20ml propyl carbinol and continues to stir 1h under 95 ℃ to 100 ℃.Evaporating solvent in a vacuum, add the 25ml2N HCl aqueous solution and 100ml ethyl acetate this mixture of vigorous stirring 1h, then suction filtration subsequently.Water thoroughly clean filter cake and under vacuum in 60 ℃ of dryings to produce the 4.43g yellow solid.Use methylene dichloride on silica gel by flash column chromatography: ethyl acetate (98:2) wash-out separates this A of 4.4g and the mixture of B.Evaporate the first elution fraction and obtain 1.99gA; 1h NMR (CDC1 3): δ=10.48 (bs, 1H), 8.39 (bs, 1H), 8.24 (d, 1H), (8.01 d, 1H), 7.35-7.55 (m, 6H), 4.39 (t, 2H), (1.77 m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).Evaporate the second elution fraction and obtain 2.26g B; 1h NMR (CDC1 3): δ=10.38 (bs, 1H), 8.32 (bs, 1H), 8.24 (d, 1H), (7.86 d, 1H), 7.37-7.56 (m, 6H), 4.39 (t, 2H), (1.77 m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).
E) the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
By 1.11g1,4-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (3mmol) is added in the solution that 4.59g bromine phosphorus oxide (16mmol) is dissolved in the 25ml anhydrous acetonitrile and by this mixture gentle reflux 1h under agitation.Then add 5.04g sodium bicarbonate (60mmol), then dropwise add 8ml water.After stirring 90min at ambient temperature, mixture is concentrated into to approximately 1/3rd of its volume in a vacuum, adds 40ml water and extract this mixture by the 30ml ethyl acetate.This mixture of suction filtration.Separate organic phase, via MgSO 4drying is also filtered by silicagel pad.Evaporation in a vacuum, produce the 0.885g title compound; 1h NMR (CDC1 3): δ=11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40-7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
F) 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation by the HI aqueous solution (3mmol) of the bromo-4-hydroxyl of 432mg1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (1mmol), 63mg red phosphorus (2mmol), 0.4ml57 % by weight and the mixture backflow 30min of 1ml Glacial acetic acid.Then, with 25ml ethyl acetate diluted reaction mixture, by the Celite pad suction filtration, use 0.2g NaHSO 3the solution that is dissolved in 5ml water cleans and uses the dense sodium bicarbonate aqueous solution of 5ml to clean twice.Via MgSO 4dry organic phase evaporation in a vacuum.By flash column chromatography hexane on silica gel: ethyl acetate (85:15) wash-out carrys out the purifying resistates.Obtain the 123mg title compound; 1h NMR (CDC1 3): δ=11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38-7.63 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
G) 2-(S)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
By 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.20g) and ALANINE (0.75g), the mixture in 0.5M NaOMe/MeOH (11.3ml) is heated to reflux, and continues 36h.After cooling, concentrated reaction mixture.Be suspended in water (50ml) by resistates and, with ethyl acetate (50ml) extraction, ethyl acetate layer abandoned with 2N HCl acidified aqueous solution water layer.Be extracted with ethyl acetate (2 * 50ml).Merge organic layer, filtration concentrated to produce title compound (0.15g) via dried over mgso.MS-(-)-ion: M-1=367.1.
Example A-64
2-(R)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-63g), by making 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester and D-alanine, react to prepare.MS-(-)-ion: M-1=367.1.
Example A-65
2-(R)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 4-phenoxy group-phthalic acid
Be similar to example A-63a) synthetic by 4-phenoxy group-phthalonitrile; MS-(-)-ion: M-1=256.9; 1h NMR (DMSO-d 6): δ=7.93 (d, 1H), 7.07-7.52 (m, 7H).
B) (1,3-dioxy-5-phenoxy group-1,3-dihydro-isoindole-2-yl)-acetic acid
Be similar to example A-63b) synthetic by 4-phenoxy group-phthalic acid.MS-(+)-ion: M+1=297.9; 1hNMR (DMSO-d 6): δ=7.87 (d, 1H), 7.17-7.52 (m, 7H), 4.26 (s, 2H).
C) (1,3-dioxy-5-phenoxy group-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to example A-63c) synthetic by (1,3-dioxy-5-phenoxy group-1,3-dihydro-isoindole-2-yl)-acetic acid; 1h NMR (CDC1 3): δ=7.83 (d, 1H), 7.05-7.46 (m, 7H), 4.41 (s, 2H), 3.76 (s, 3H).
D) Isosorbide-5-Nitrae-dihydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to example A-63d) synthetic by (1,3-dioxy-5-phenoxy group-1,3-dihydro-isoindole-2-yl)-methyl acetate; Compd A: 1h NMR (CDCl 3): δ=10.58 (bs, 1H), 8.37 (bs, 1H), 8.14 (d, 1H), (7.87 d, 1H), 7.05-7.49 (m, 6H), 4.39 (t, 2H), (1.77 m, 2H), 1.46 (m, 2H), 0.99 (t, 3H); Compd B: 1h NMR (CDCl 3): δ=10.38 (bs, 1H), 8.38 (d, 1H), 8.28 (bs, 1H), (7.56 d, 1H), 7.06-7.47 (m, 6H), 4.40 (t, 2H), (1.77 m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).
E) the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-63e), by l, 4-dihydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1h NMR (CDCl 3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08-7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
F) 4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Stir the mixture 15h of the bromo-4-hydroxyl of 208mg1--7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (0.5mmol), 49mg sodium acetate (0.6mmol), 50mg10 % by weight palladium charcoal, 10ml methyl alcohol and 5ml ethyl acetate in 1atm under hydrogen.Then by this mixture of Celite pad suction filtration concentrated in a vacuum.Make to divide between the resistates bicarbonate aqueous solution concentrated at 2ml half and 8ml ethyl acetate molten.Via MgSO 4dry organic phase.Evaporate in a vacuum and produce the 130mg title compound; 1h NMR (CDCl 3): δ=11.89 (bs, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10-7.53 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
G) 2-(R)-[(4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-63g), by under refluxad being reacted over 5 days, 4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester and D-alanine prepare.MS-(-)-ion: M-1=351.1.
Example A-66
2-(S)-{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 4-(4-methoxyl group-phenoxy group)-phthalonitrile
4-nitro-phthalonitrile (4.00g), 4-methoxyl group-phenol (3.46g) and the mixture of salt of wormwood (6.39g) in acetone (64ml) are heated to reflux, continue 2h.Reaction mixture is also filtered.Filtrate is concentrated and resistates is dissolved in ethyl acetate (100ml).Also then with salt solution, clean this solution with NaOH (1N, 50ml), water.Merge organic layer, filtration concentrated to produce product (6.14g) via dried over mgso. 1H NMR(200MHz,CDCl 3)δ6.70(d,J=7.8Hz,1H),7.21(m,2H),6.96(m,4H),3.84(s,3H)。
B) 4-(4-methoxyl group-phenoxy group)-phthalic acid
Be similar to example A-63a) prepare.MS-(-)-ion: M-1=286.9.
C) [5-(4-methoxyl group-phenoxy group)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
Be similar to example A-63b) and c) prepare. 1H NMR(200MHz,CDC1 3)δ7.74(d,J=8.6Hz,1H),7.25(m,2H),6.98(m,4H),4.40(s,2H),3.83(s,3H),3.75(s,3H)。
D) 6-and 7-(4-methoxyl group-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-63d) prepare.MS-(+)-ion: M+1=384.10.
E) the bromo-4-hydroxyl of 6-and 7-(4-methoxyl group-phenoxy group)-1--isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-63e) prepare.MS-(+)-ion: M+1=448.05,446.05.
G) 7-(4-methoxyl group-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (A) and 6-(4-methoxyl group-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (B)
10 % by weight palladium charcoals (wetting) (1.2g) are added in ethyl acetate (50ml) solution of above-claimed cpd (2.78g) and then add ammonium formiate (5.9g).The mixture 4h of backflow gained.After cooling, by its filtration and by ethyl acetate (100ml), rinse.Filtrate is concentrated and pass through silica gel chromatography (33%-50% ethyl acetate in hexane) purifying resistates to produce (0.74g) (MS-(+)-ion: M+1=368.16) and (1.11g) (MS-(+)-ion: M+1=368.17) of 6-(4-methoxyl group-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (B) of 7-(4-methoxyl group-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (A).
H) 2-(S)-{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to example A-63g), by (example A-66a's) 7-(4-methoxyl group-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and ALANINE, prepared.MS-(-)-ion: M-1=381.13.
Example A-67
2-(S)-[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 7-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
By 7-phenyl sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound 363f) (165mg) and (377mg) stirred overnight at room temperature of the mixture in methylene dichloride (5ml) of m-chlorine peroxybenzoic acid (77%).Filter reaction mixture.With methylene dichloride (20ml) dilution filtrate saturated sodium bicarbonate aqueous solution (2 * 20ml), water and salt solution cleaning for continuation.Via dried over mgso organic layer, filtration concentrated.By silica gel chromatography (with the 0%-20% eluent ethyl acetate in methylene dichloride) purification of crude product to produce title compound 120mg.MS-(+)-ion: M+1=386.11.
B) 2-(S)-[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-63g), by 7-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and ALANINE, prepared.MS-(-)-ion: M-1=399.1.
Example A-68
(R)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid
Under agitation by the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (3.52g, 8.45mmol; Example A-65e), the mixture backflow 2h of the 2N NaOH aqueous solution (50ml, 100mmol) and EtOH (50ml).Then concentrated this solution is to the l/2 of its volume in a vacuum, and water (180ml) dilute and passes through the acidifying of the interpolation 6N HCl aqueous solution (20ml).Make the vacuum filtration of gained suspension after stirring at ambient temperature 30min.Water thoroughly clean filter cake in a vacuum in 70 ℃ of dryings with the be white in color title compound (3.05g) of solid of generation; 1hNMR (DMSO-d 6): δ=8.33 (d, 1H), 7.20-7.61 (m, 7H).
B) 4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester
Under agitation in-78 ℃ of hexanes by the 2.5M n-Butyl Lithium (3.2ml, 8mmol) solution, slowly be added in anhydrous THF (100ml) solution of the bromo-4-hydroxyl of l--7-phenoxy group-isoquinoline-3-carboxylic acid (721mg, 2mmol).Add MeOCH after stirring 5min again 2i (357 μ l, 4mmol).15min is stirred again in continuation under-78 ℃, then adds water (50ml) and the 6N HCl aqueous solution (1.5ml).Under agitation make this mixture temperature to envrionment temperature and then be concentrated in a vacuum approximately 1/3 of its volume.Remove micro-iodine by adding Sodium Pyrosulfite, then use EtOAc (100ml) to extract this mixture.Via MgSO 4dry organic phase is also concentrated to produce brown color solid (576mg) in a vacuum.The above-mentioned micro-yellow solid of the 570mg that under agitation refluxes, bromotoluene (0.97ml, 8mmol), K 2cO 3the mixture of (2.76g, 20mmol) and acetone (40ml) 3.5 days.Then concentrated in a vacuum.Water (15ml) is added in resistates and extracts this mixture with EtOAc (60ml).Via MgSO 4dry organic phase is also concentrated to produce micro-yellow oil in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=75:25 carrys out purifying as elutriant, produces the title compound (490mg) that is yellow oil; MS-(+)-ion: M+1=506.2.
C) 4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid
Stir at ambient temperature the mixture 48h of 4-phenoxy group-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester (480mg, 0.95mmol), KOH (325mg, 5mmol) and EtOH (10ml), then evaporating solvent in a vacuum.Water (10ml) is added in resistates, by adding the 6N HCl aqueous solution, carrys out this mixture of acidifying and extract with EtOAc (2 * 25ml).Via MgSO 4the dry organic phase that merges also concentrates the title compound (355mg) that is the brown color solid with generation in a vacuum; MS-(-)-ion: M-1=414.1.
D) (R)-2-[(4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-the propionic acid tert-butyl ester
Under agitation by ClCO 2iBu (26.5 μ l, 0.2mmol) is added into the 4-benzyloxy cooling with ice bath-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid (79mg, 0.19mmol), NEt 3(56 μ l, 0.4mmol) and CH 2cl 2(5ml) in mixture.After stirring 15min, add (R)-L-Ala tert-butyl ester hydrochloride (36mg, 0.2mmol) and under agitation by this mixture temperature to envrionment temperature whole night.Concentrate in a vacuum subsequently this mixture.Water (10ml) and several 6N HCl aqueous solution are added in resistates.Extract this mixture with EtOAc (2 * 15ml).Via MgSO 4dry organic phase is also concentrated in a vacuum.Carry out purifying with EtOAc as elutriant by flash column chromatography on silica gel, produce the title compound (88mg) that is brown color oil; MS-(+)-ion: M+23=565.2.
E) (R)-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-tert.-butyl acetate
At H 2stir (R)-2-[(4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl under-atmosphere at environmental stress and temperature)-amino]-the propionic acid tert-butyl ester (81mg, 0.15mmol), the mixture 18h of Pd/C (50mg, 10 % by weight Pd), EtOAc (15ml).Then by Celite pad, filter this mixture.Thoroughly clean diatomite and filter cake and concentrate in a vacuum the merging organic phase with EtOAc and be the title compound (63mg) of brown color oil with generation; MS-(-)-ion: M-1=451.2.
F) (R)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Stir at ambient temperature the mixture 4h of (R)-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-tert.-butyl acetate (59mg, 0.13mmol) and trifluoroacetic acid (4ml).Then concentrate in a vacuum this mixture and resistates is dissolved in EtOH.Evaporating solvent is the title compound (52mg) of brown color solid with generation in a vacuum; MS-(+)-ion: M+1=397.1.
Example A-69
(S)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) (S)-2-[(4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-the propionic acid tert-butyl ester
Be similar to example A-68d), synthetic by (S)-L-Ala tert-butyl ester and 4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid (example A-68c); MS-(+)-ion: M+23=565.2.
B) (S)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-the propionic acid tert-butyl ester
Be similar to example A-68e), by (S)-2-[(4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-the propionic acid tert-butyl ester is synthetic; MS-(-)-ion: M-1=451.2.
C) (S)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-68f), by (S)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-the propionic acid tert-butyl ester is synthetic; MS-(+)-ion: M+1=397.1.
Example A-70
(S)-2-[(4-sulfydryl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 4-dimethyl thiocarbamyl oxygen base-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
By the 578mg dimethyl sulphide, for chloroformamide and 1.5g1,4-diazabicyclo [2.2.2] octane is added into 1.5g4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (example A-65f) and is dissolved in the solution of 6.3ml dry DMF.At room temperature stir whole night this mixture.Mixture is injected to 30ml 1N HCl and divides 3 extractions by the 30ml ethyl acetate.Water and salt solution clean organic part, via anhydrous sodium sulfate drying concentrated to produce the 1.9g product; MS (+) m/z425.27 (M+1).
B) 4-dimethylamino formyl radical sulfenyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
The solution that 1.9g4-dimethyl thiocarbamyl oxygen base-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is dissolved in to the 22ml phenyl ether is heated to 190 ℃, continues 2 hours.Under vacuum, concentrated this solution is to produce thick resistates, and it carrys out purifying with this product of 30-80% ethyl acetate gradient elution in hexane by column chromatography on silica gel, produces 1.73g; MS (+) m/z425.07 (M+1).
C) 4-sulfydryl-7-phenoxy group-isoquinoline-3-carboxylic acid methyl esters
460mg4-dimethylamino formyl radical sulfenyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is added in the methanol solution of 6.5ml0.5N sodium methylate.Gained solution is heated to 50-60 ℃, continues 8 hours, be cooled to room temperature and dilute with 10ml water and 7.0ml 1N HCl.Filter by (medium) porous Bu Shi filter funnel the yellow mercury oxide that this solution is collected gained, produce the 307mg product; MS (+) m/z312.08 (M+1).
D) (S)-2-[(4-sulfydryl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
100mg4-sulfydryl-7-phenoxy group-isoquinoline-3-carboxylic acid methyl esters and 286mg ALANINE are added in the methanol solution of 6.0ml0.5M sodium methylate.Use CEM Discover microwave reactor that this mixture is heated to 150 ℃, continue 15min.With 1N HCl, gained solution is acidified to pH3, with 10ml water, dilutes and use the 20ml ethyl acetate to extract.Clean organic part with salt solution, via anhydrous sodium sulfate drying concentrated to produce the 114mg product; MS (-): m/z369.07 (M-1).
Example A-71
(S)-2-{[1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) the bromo-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-65c)-e), by (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate, prepare title compound; 1h NMR (200MHz, CD 3oD) δ 11.89 (s, lH), 8.41 (m, 1H), 8.25 (m, 1H), 7.84 (m, 2H), 4.49 (t, J=7.0Hz, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 1.00 (t, J=7.2Hz, 3H).
B) (S) the bromo-4-hydroxyl-isoquinoline 99.9 of-2-{[1--3-carbonyl]-amino }-propionic acid
The bromo-4-hydroxyl of 400mg1--isoquinoline-3-carboxylic acid butyl ester and 890mg (L)-L-Ala are suspended in the methanol solution of 20ml0.5M sodium methylate.Use CEM Discover microwave reactor that this mixture is heated to 160 ℃, continue 12min.Gained solution is concentrated into to about 10ml, and adds 0.5N HCl until reach pH3.Be extracted with ethyl acetate this solution 3 times, and organic part and be concentrated into the brown color solid via dried over sodium sulfate; MS (-): m/z337.14 (M-1).
C) (S)-2-{[1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
The chloro-benzenethiol of 433mg4-is added into to the bromo-4-hydroxyl-isoquinoline 99.9 of 250mg (S)-2-{[1--3-carbonyl]-amino }-propionic acid is dissolved in the solution of 0.7ml1-N-methyl-2-2-pyrrolidone N-.Use CEM Discover microwave reactor that this solution is heated to 30min under 210 ℃.Concentrated this solution under vacuum.From methyl alcohol, crystallization gained resistates is to obtain 18mg brown color solid; MS (-): m/z401.10 (M-1).
Example A-72
(R)-2-{[1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Prepare title compound by the bromo-4-hydroxyl of l--isoquinoline-3-carboxylic acid butyl ester (example A-71a) and (D)-L-Ala under the condition that is similar to example A-71.b-c; MS (-): m/z401.08 (M-1).
Example A-73
(S)-2-{[7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 4-(the fluoro-phenoxy group of 3,4-bis-)-phthalonitrile
Be similar to example A-60a) prepare. lH NMR(200MHz,DMSO)δ8.14(d,J=9Hz,1H),7.95(d,J=2.6,1H),7.56(dd,J=2.6,8.6Hz,1H),7.19(dt,J=2.4,9.2Hz,1H),7.04(m,2H)。
B) 4-(the fluoro-5-methoxyl group-phenoxy group of 3-)-phthalic acid
Be similar to example A-60b) prepare.In hydrolysis, one fluorine-based by methoxy substitution.MS-(-)-ion, M-1=305.0.
C) [5-(the fluoro-5-methoxyl group-phenoxy group of 3-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
Be similar to example A-60c) prepare. 1H NMR(200MHz,DMSO)δ7.93(d,J=8.6Hz,1H),7.43(m,2H),6.79-6.63(m,3H),4.41(s,2H),4.10(t,J=6.2,2H),1.54(m,2H),1.30(m,2H),0.86(t,J=7.0,3H)。
D) 6-and 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-2b) prepare.The mixture of two kinds of isomer.MS-(-)-ion, M-1=400.1.
E) the chloro-6-of 1-and 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-2c) prepare.The mixture of two kinds of isomer.MS-(-)-ion, M-1=418.3.
F) 6-and 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-62e) prepare.The mixture of separating isomerism body is to produce 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of example A-73a) and 6-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of example A-73b). 1H NMR(200MHz,CD 3OD)δ8.73(s,1H),8.15(d,J=9.0Hz,1H),7.71(s,1H),7.59(m,1H),6.65-6.47(m,3H),4.49(t,J=6.6Hz,2H),3.81(s,3H),1.87(m,2H),1.56(m,2H),1.03(t,J=7.4,3H)。
G) (S)-2-{[7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to example A-50, by prepared over 3 days in 90 ℃ of reactions by 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of example A-73a) and ALANINE in penstock.MS-(-)-ion: M-1=399.1.
Example A-74
2-(S)-[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (5-hydroxyl-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate
Be similar to example D-100c), by 4-hydroxyl-phthalic acid and the preparation of glycine ethyl ester acetate. 1H NMR(200MHz,DMSO-d 6)δ11.0(br s,1H),7.74(d,J=7.8Hz,1H),7.17(m,2H),4.35(s,2H),4,13(q,J=7.0Hz,2H),1.20(t,J=7.0Hz,3H)。
B. (5-cyclohexyloxy-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate
Hexalin (3.2g), diethyl azodiformate (6.9g) are added into to (5-hydroxyl-1,3-dioxy-1,3-dihydro-isoindole-2-yl) in-mixture of ethyl acetate (8.0g) in anhydrous tetrahydro furan (160ml) and then add triphenylphosphine (12.6g).At room temperature stir whole night gained mixture concentrated.Resistates is divided between water and ethyl acetate molten.Be extracted with ethyl acetate water layer.Clean and merge organic phase with salt solution, via dried over mgso filtration.Concentrating filtrate also passes through silica gel chromatography (with 5% eluent ethyl acetate in methylene dichloride) purifying to produce title compound 6.2g. 1H NMR(200MHz,CDC1 3)δ7.73(dd,J=8.2,0.8Hz,1H),7.30(br s,1H),7.12(m,1H),4.38(m,3H),4.21(q,J=7.1Hz,2H),2.02(m,2H),1.82-1.25(m,13H)。
C.6-with 7-cyclohexyloxy-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-63d) prepare, produce 7-cyclohexyloxy-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (compd A-74c1) (MS-(+)-ion M+1=360.16) and 6-cyclohexyloxy-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (compd A-74c2) (MS-(+)-ion M+1=360.18).
D.1-bromo-7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Heat 7-cyclohexyloxy-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl esters (compd A-74c1) (1.3g) and the mixture 15min of bromine phosphorus oxide (1.35g) in dry toluene (25ml) in 130 ℃ in microwave reactor (sealed tube).After cooling, concentrated reaction mixture.Process resistates and at room temperature stir 20min with saturated sodium bicarbonate aqueous solution (100ml).Organic layer water, salt solution are cleaned, via dried over mgso, filtration concentrated to produce title compound (1.2g).MS-(+)-ion M+1=422.12,424.12.
E.7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
10%Pd/C (50% is wet) (430mg) is added in the bromo-7-cyclohexyloxy of the l--4-hydroxyl-mixture of isoquinoline-3-carboxylic acid butyl ester (936mg) in ethyl acetate (25ml) and then adds ammonium formiate (1.4g).Backflow gained mixture 4h.After cooling, filter reaction mixture concentrated.By silica gel chromatography (the 3%-10% ethyl acetate in methylene dichloride) purifying resistates to produce title compound (550mg).MS-(+)-ion, M+1=344.22.
F.2-(S)-[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Mixture 40min in microwave reactor (sealed tube) in 120 ℃ of heating 7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl esters (80mg) and methyl alcohol (3.7ml) solution of ALANINE (207mg) at the 0.5M sodium methylate.Concentrated reaction mixture, also be acidified to pH=4 with 2N HCl in water-soluble (30ml).Be extracted with ethyl acetate.Water, salt solution clean and merge organic phase, via dried over mgso filtration.Concentrating filtrate also produces title compound (52mg) by the silica gel chromatography purifying.MS-(+)-ion, M+1=359.18.
Example A-75
2-(S)-{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A.5-(the fluoro-phenoxy group of 4-)-isoindole-1, the 3-diketone
5-nitro-isoindole-1 of under agitation refluxing, 3-diketone (177g, 0.904mol), the fluoro-phenol of 4-(128g, 1.13mol), K 2cO 3the mixture 3h of (419g, 3mol) and DMF (2l), then under agitation by this mixture injected water (12l).By formed throw out, by isolated by vacuum filtration, water (8l) cleans and also is in a vacuum the title compound (43.2g) of brown color powder in 70 ℃ of dryings with generation; 1hNMR (CDC1 3) δ=7.79 (d, 1H), 7.57 (br s, 1H), 7.01-7.29 (m, 6H).
B.[5-(the fluoro-phenoxy group of 4-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
5-(the fluoro-phenoxy group of 4-)-isoindole-1 of under agitation refluxing, 3-diketone (42.9g, 167mmol), bromo-methyl acetate (21.1ml, 223mmol), K 2cO 3(62.3g, 446mmol) and Et 2the mixture 16h of CO (700ml), then concentrate this mixture in a vacuum.Be added in resistates by water (150ml) and use EtOAc (1 * 750ml, 1 * 250ml) to extract the slurries of gained.Via MgSO 4the dry organic phase that merges also concentrates the title compound (49.7g) that is the brown color solid with generation in a vacuum; 1h NMR (CDCl 3) δ=7.80 (d, 1H), 7.01-7.30 (m, 6H), 4.41 (s, 2H), 3.76 (s, 3H).
C.7-(the fluoro-phenoxy group of 4-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation in 70 ℃, sodium (7.2g, 310mmol) is dissolved in propyl carbinol (300ml).Then temperature is risen to 95-100 ℃ and add [5-(the fluoro-phenoxy group of 4-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate (49.4g, 150mmol) be dissolved in the solution in hot propyl carbinol (300ml) under vigorous stirring.Stir the other 90min of this mixture and then under agitation make it be cooled to 60 ℃ under 95-100 ℃, then adding 2N HCl (160ml).This mixture of vigorous stirring 30min also then makes it be cooled to envrionment temperature.Subsequently, make this mixture vacuum filtration.Water thoroughly clean filter cake and under vacuum in 70 ℃ of dryings to produce light yellow solid.Use CH on silica gel by flash column chromatography 2cl 2: EtOAc=98:2 comes purifying to produce title compound (14.4g, first part) as elutriant; 1h NMR (CDCl 3) δ=8.40 (br s, 1H), 8.14 (d, 1H), 7.80 (d, 1H), (7.42-7.48 m, 1H), 7.04-7.14 (m, 4H), 4.39 (t, 2H), (1.70-1.85 m, 2H), 1.37-1.55 (m, 2H), 0.99 (t, 3H).
D.1-bromo-7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation gentle reflux 7-(the fluoro-phenoxy group of 4-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (14.33g, 38.6mmol), POBr 3the mixture 75min of (44.7g, 154.4mmol) and anhydrous methyl-cyanide (290ml), then under agitation a small amount of by a part interpolation NaHCO 3(100.8g, 1.2mol).Under agitation slowly add subsequently water (200ml) this mixture of vigorous stirring 1h at ambient temperature, then be concentrated in a vacuum about 1/2 of its volume.Then add water (200ml) and extract this mixture with EtOAc (1 * 400ml, 1 * 200ml).Via MgSO 4the dry organic phase that merges also evaporates to produce the brown color solid in a vacuum.This brown color solid is dissolved in to CH 2cl 2in and filter purifying by silica gel plug.Concentrated gained CH in vacuum 2cl 2solution obtains title compound (11.4g); 1h NMR (CDCl 3) δ=11.89 (s, 1H), 8.36 (d, 1H), 7.57 (d, 1H), (7.44-7.50 m, 1H), 7.08-7.16 (m, 4H), 4.47 (t, 2H), (1.78-1.93 m, 2H), 1.38-1.58 (m, 2H), 0.99 (t, 3H).
E.7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
The bromo-7-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (434mg, 1mmol), Pd (PPh under agitation reflux 3) 4(116mg, 0.1mmol), trimethylboroxin (140 μ l, 1mmol), K 2cO 3the mixture 2h of (414mg, 3mmol) and Isosorbide-5-Nitrae-dioxane (8ml).Concentrate in a vacuum subsequently this mixture.Water (10ml) is added in resistates.By adding 6N HCl this mixture of acidified aqueous solution and then extracting with EtOAc (40ml).Via MgSO 4dry organic phase evaporation in a vacuum.By flash column chromatography, on silica gel, use hexane: EtOAc=94:6 to carry out the purifying resistates as elutriant, produce the title compound (229mg) of the solid that is white in color; MS-(+)-ion: M+1=370.1.
F.2-(S)-{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
In microwave oven under stirring 140 ℃ of heating 7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (92mg, 0.25mmol), (S)-L-Ala (225mg, 2.5mmol) and the MeOH solution (5ml of 0.5N MeONa, 2.5mmol) mixture 20min, concentrated this mixture in a vacuum then.Water (10ml) is added in resistates and cleans this mixture with EtOAc (2 * 25ml).By the aqueous solution that adds the such purifying of 6N HCl acidifying, also with EtOAc (1 * 25ml), extract.Via MgSO 4dry organic phase also concentrates the title compound (69mg) that is the brown color solid with generation in a vacuum; MS-(+)-ion: M+1=385.1.
Example A-76
2-(S)-{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A.7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
At H 2stir the bromo-7-of l-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (4.34g under-atmosphere at environmental stress and temperature, 10mmol, see example A-75d), sodium acetate (984mg, 12mmol), Pd/C (2.0g, 10 % by weight Pd, 50 % by weight water), the mixture 2.5h of EtOAc (400ml) and MeOH (200ml), then by plug of celite, filter this mixture.Clean diatomite with EtOAc (500ml).Concentrate in a vacuum and merge organic phase.Will half concentrated NaHCO 3solution (50ml) is added in resistates and uses CH 2cl 2(1 * 200ml) extracts this mixture.Via MgSO 4dry organic phase also concentrates the title compound (3.45g) to obtain being brown color oil in a vacuum; MS-(+)-ion: M+1=356.1.
B.2-(S)-{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
In microwave oven under stirring 130 ℃ of heating 7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (154mg, 0.43mmol), (S)-L-Ala (225mg, 2.5mmol) and the MeOH solution (5ml of 0.5N MeONa, 2.5mmol) mixture 20min, concentrated this mixture in a vacuum then.Water (15ml) is added in resistates and uses Et 2o (3 * 30ml) cleans this mixture.By the aqueous solution that adds 6N HCl acidifying purifying, also with EtOAc (1 * 30ml), extract.Via MgSO 4dry organic phase also concentrates the title compound (79mg) that is the brown color solid with generation in a vacuum; MS-(-)-ion: M-1=369.1.
Example A-77
2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A.1-chloro-4-hydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester and 1-chloro-4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (regional isomerism mixture)
By l, 4-dihydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester and l, the regional isomerism mixture of 4-dihydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (40.63g, 115mmol are shown in example A-65d) is added into POCl 3(300ml) in.Under agitation this mixture of gentle reflux 30min, then concentrated in a vacuum.Be dissolved in EtOAc (800ml) by resistates and add water (400ml).Then by NaHCO 3(about 100g) is added in the mixture of vigorous stirring by part on a small quantity.Stir at ambient temperature subsequently this mixture 1h, then filter by Celite pad.Separate organic phase, via MgSO 4drying also evaporates to produce the brown color solid in a vacuum.This brown color solid is dissolved in to CH 2cl 2in and filter purifying by silica gel plug.The CH of concentrated gained in vacuum 2cl 2the title compound (15.51g) of solution to obtain being the brown color solid; MS-(-)-ion M-1=370.2.
B.4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
By l-chloro-4-hydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester and l-chloro-4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (11.15g, regional isomerism mixture 30mmol) is added into anhydrous Isosorbide-5-Nitrae-dioxane (200ml), Pd (PPh 3) 4(3.47g, 3mmol), trimethylboroxin (4.22ml, 30mmol) and K 2cO 3in the mixture of (12.44g, 90mmol).At N 2also then stir at ambient temperature 48h in stirring lower this mixture 3h that refluxes under-protection.Subsequently, concentrate in a vacuum this mixture.Water (100ml) is added in resistates and extracts this mixture with EtOAc (300ml).Via MgSO 4dry organic phase evaporation in a vacuum.By flash column chromatography, on silica gel, use hexane: EtOAc=9:1 to carry out the purifying resistates as elutriant, produce the title compound (4.40g, first part) that is micro-yellow solid; MS-(+)-ion: M+1=352.1.
C.2-(S)-[(4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
In microwave oven under stirring 120 ℃ of heating 4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (176mg, 0.5mmol), (S)-L-Ala (225mg, 2.5mmol) and the MeOH solution (5ml of 0.5N MeONa, 2.5mmol) mixture 20min, concentrated this mixture in a vacuum then.Water (15ml) is added in resistates and uses Et 2o (3 * 30ml) cleans this mixture.Carry out the aqueous solution of the such purifying of acidifying and extract with EtOAc (1 * 30ml) by adding 6N HCl.Via MgSO 4dry organic phase also concentrates the title compound (108mg) that is the brown color solid with generation in a vacuum; MS-(-)-ion: M-1=365.1.
Example A-78
2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid
Stir Isosorbide-5-Nitrae-dihydroxyl in the 600ml anhydrous acetonitrile-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (example A-63d) compd A under refluxing) (29.0g) and bromine phosphorus oxide (67.5g) 4 hours.After cooling, concentrated reaction mixture also is added into saturated sodium bicarbonate solution and ethyl acetate in resistates and stirs whole night.The throw out the water that are collected in interlayer formation clean to produce title compound (10.2g).MS-(+)-ion M+1=376.0,378.1.
B) the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters
By the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid (10.0g), salt of wormwood (3.7g) and methyl-sulfate (3.4g), be suspended in 500ml acetone and stirred overnight under refluxing.Concentrated reaction mixture also makes resistates minute molten between 1N hydrochloric acid and ethyl acetate.Via dried over mgso organic layer filtration.Concentrating filtrate is to produce title compound (9.6g).MS-(+)-ion M+1=389.9,391.9.
C) 4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters
The bromo-4-hydroxyl of 1-in microwave reactor (sealed tube) in 140 ℃ of heating Isosorbide-5-Nitrae-dioxanes (4ml)-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters (0.2g), tetrakis triphenylphosphine palladium (60mg), methyl boroxane (65mg) and salt of wormwood 10min.After cooling, concentrated reaction mixture also divides molten between 1N hydrochloric acid and ethyl acetate.Via dried over mgso organic layer filtration.Concentrating filtrate also separates to produce title compound (47mg) by silica gel chromatography (with 2% eluent ethyl acetate in methylene dichloride).MS-(+)-ion M+1=326.1.
D) 2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to example A-74f) prepare. 1H NMR(200MHz,DMSO-d 6)δ13.26(br s,1H),9.07(s,1H),8.61(s,1H),8.33(d,J=8.2Hz 1H),7.97(d,J=8.6Hz,1H),7.81(br s,2H),7.52(br s,3H),4.52(br s,1H),2.91(s,3H),1.49(d,J=7.0Hz,3H)。
Example A-79
2-(S)-{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 4-(4-trifluoromethyl-phenoxy group)-phthalonitrile
Be similar to example A-66a) prepare. 1H NMR(200MHz,CDC1 3)δ7.74(m,2H),7.47(d,J=8.6Hz,1H),7.25(m,3H),6.87(d,J=8.9Hz,1H)。
B) 4-(4-trifluoromethyl-phenoxy group)-phthalic acid
Be similar to example A-66b) prepare. 1H NMR(200MHz,DMSO-d 6)δ8.24(d,J=9.0Hz,1H),7.75(m,3H),7.19(m,3H)。
C) [1,3-dioxy-5-(4-trifluoromethyl-phenoxy group)-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to example A-66c) prepare. 1H NMR(200MHz,CDC1 3)δ7.86(d,J=8.5Hz,1H),7.67(d,J=8.2Hz,2H),7.40-7.13(m,4H),4.43(s,2H),3.769s,3H)。
D) 7-(4-trifluoromethyl-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-66d) prepare.Separate two kinds of isomer to produce title compound by chromatography.MS-(+)-ion M+1=422.0.
E) 1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-2c) prepare.MS-(-)-ion M-1=438.3.
F) 4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example A-74e) prepare.MS-(+)-ion M+1=406.1.
G) 2-(S)-{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to example A-74f) prepare.MS-(+)-ion M+1=421.2.
Example B-1
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides; Three fluoro-acetates
A. (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-butylacetate
The mixture of 160ml butanols, 20.0g (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetic acid (94.6mmol) and the 2.0ml vitriol oil 24h that under agitation refluxes.Then by part adding a 5g sodium bicarbonate, continue at room temperature to stir 5min evaporating solvent in a vacuum.Resistates is divided in 100ml water and 100ml ethyl acetate molten.Clean organic phase with 100ml salt solution, via dried over sodium sulfate, also evaporate in a vacuum to produce the micro-yellow oil with after coagulation.Obtain the 24.02g title compound; MS-(+)-ion M+1=261.9.
B.1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation 4.41g sodium (190mmol) is dissolved in the 250ml propyl carbinol.After sodium dissolves fully, make solution be cooled to envrionment temperature and under agitation add 24.0g (91.9mmol) (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-butylacetate and be dissolved in the solution of 150ml butanols.This solution is heated to 100 ℃ and stir 1h at this temperature in 30min.Then make this compound be cooled to envrionment temperature and store at ambient temperature 18h.Then by under agitation adding the 2N aqueous hydrochloric acid, the pH value of compound is adjusted into to 2 to 3.Continue to stir 30min, then suction filtration solid ingredient.Water thoroughly clean filter cake and under vacuum in 50 ℃ of dryings to produce white solid.Obtain the 17.75g title compound; MS-(+)-ion: M+1=262.1.
C.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Stir at ambient temperature the mixture 1h of 17.3g (66.2mmol) Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester and 100ml phosphorus oxychloride and then under agitation in 2h, slowly be heated to reflux temperature.This mixture of gentle reflux 30min under agitation.After being cooled to room temperature, evaporating in a vacuum excessive phosphorus oxychloride and resistates is dissolved in the 100ml ethyl acetate.This solution is under agitation injected to the 300ml saturated sodium bicarbonate aqueous solution.Formed throw out removes by vacuum filtration.Separate organic phase and by the ethyl acetate aqueous phase extracted of 3 * 100ml.Merge water via dried over sodium sulfate, by silicagel pad, filter and also evaporate in a vacuum to produce the brown oil with after coagulation.Obtain the 11.37g title compound; 1h NMR (CDC1 3): δ=11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
D.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid
The mixture 2h of 9.23g1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (33mmol), 90ml2.5N aqueous sodium hydroxide solution, water (20ml) and the ethanol (110ml) of under agitation refluxing.Then by adding concentrated hydrochloric acid aqueous solution, the pH value of mixture is adjusted into to 2.In adding procedure, by by the cooling temperature of mixture that makes of ice bath, remaining on 20 ℃.Then continue to stir 1h, then by the isolated by vacuum filtration solid ingredient.Water clean filter cake and under vacuum in 85 ℃ of dryings to produce white powder.Obtain the 6.64g title compound; MS-(+)-ion: M+1=224.1.
E.{2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-ethyl }-t-butyl carbamate
96 μ l (0.55mmol) ethyl-di-isopropyls-amine under agitation is added in the mixture of 45mg (0.2mmol) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid, 76mg (0.2mmol) phosphofluoric acid benzotriazole-1-base-(two-dimethylamino-methylene radical)-oxygen (HBTU), 32 μ l (2-amino-ethyl)-t-butyl carbamate (0.2mmol) and 1ml methylene dichloride.Continue to stir at ambient temperature 5 days.Use hexane: ethyl acetate (8:2) is as elutriant, by flash column chromatography on silica gel from reaction mixture separated product to produce pale brown coloring agent.Obtain the 8mg title compound; MS-(-)-ion: M-1=364.0.
F.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides; Three fluoro-acetates
Stir at ambient temperature 8mg (0.022mmol) 2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-ethyl-the mixture 2h of t-butyl carbamate and 2ml trifluoroacetic acid.Then evaporate in a vacuum excessive trifluoroacetic acid, be dissolved in dehydrated alcohol by resistates and concentrate in a vacuum this solution to produce the brown color solid.Obtain the 8.5mg title compound; MS-(+)-ion: M+1=266.0.
Example B-2
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides
96 μ l (0.55mmol) ethyl-di-isopropyls-amine under agitation is added in the mixture of 45mg (0.2mmol) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (from example A-1d), 76mg (0.2mmol) phosphofluoric acid benzotriazole-1-base-(two-dimethylamino-methylene radical)-oxygen (HBTU), 18 μ l2-methoxyl group-ethamine (0.2mmol) and 1ml methylene dichloride.Continue to stir at ambient temperature 12 days.Use hexane: ethyl acetate (9:1) is as elutriant, by flash column chromatography on silica gel from reaction mixture separated product to produce white solid.Obtain the 8.8mg title compound; MS-(+)-ion: M+1=281.0.
Example B-3
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides
Be similar to example 2, by from example A-1d) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and 2-amino-ethanol synthesize; MS-(-)-ion: M-1=265.2.
Example B-4
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides
At ambient temperature by 28mg (0.1mmol) from example A-1c) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester, 116 μ l (1mmol) N, N-dimethyl-ethyl-1, the mixture of the dehydrated alcohol of 2-diamines and 0.5ml stirs 18h.Follow evaporating solvent in a vacuum, resistates is suspended in 5ml water and by the ethyl acetate of 2 * 35ml and extracts mixture.Merge organic phase and evaporate in a vacuum to produce micro-yellow solid via dried over sodium sulfate.Obtain the 29mg title compound; MS-(+)-ion: M+1=294.1.
Example B-5
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-acetylaminohydroxyphenylarsonic acid ethyl)-acid amides
Stir at ambient temperature 56mg from example B-1c) the mixture 3 days of (0.2mmol) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester, 227mg (2mmol) N-(2-amino-ethyl)-ethanamide and 0.8ml dehydrated alcohol.Follow evaporating solvent in a vacuum, resistates is suspended in 3ml water, and by adding the 1N HCl aqueous solution, the pH value of this mixture is adjusted into to 2 to 3.Extract this mixture by 2 * 25ml ethyl acetate.Merge organic phase and evaporate in a vacuum to produce micro-yellow solid via dried over sodium sulfate.Obtain the 64mg title compound; MS-(+)-ion: M+1=308.1.
Example B-6
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides
Be similar to example B-5, synthesized by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can obtain according to the people's such as Weidmann United States Patent (USP) 6,093,730,10/1998) and 2-amino-ethanol; MS-(+)-ion: M+1=325.1.
Example B-7
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides
Be similar to example B-5, synthesized by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can obtain according to the people's such as Weidmann United States Patent (USP) 6,093,730,10/1998) and 2-methoxyl group-ethamine; MS-(+)-ion: M+1=339.0.
Example B-8
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides; Three fluoro-acetates
Be similar to example B-5, (can be according to the people's such as Weidmann United States Patent (USP) 6 by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester, 093,730,10/1998 obtains) and (2-amino-ethyl)-t-butyl carbamate synthesize, then be similar to example B-1f) carry out deprotection; MS-(+)-ion: M+1=324.1.
Example B-9
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides
Be similar to example B-4, (can be according to the people's such as Weidmann United States Patent (USP) 6,093 by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester, 730,10/1998 obtain) and N, N-dimethyl-ethyl-1, the 2-diamines synthesizes, and then is similar to example B-1f) carry out deprotection; MS-(+)-ion: M+1=352.1.
Example B-10
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides; Three fluoro-acetates
Be similar to example B-5, (can be according to the people's such as Weidmann United States Patent (USP) 6 by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester, 093,730,10/1998 obtains) and (2-amino-ethyl)-t-butyl carbamate synthesize, then be similar to example B-1f) carry out deprotection; MS-(+)-ion: M+1=324.0.
Example B-11
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides
Be similar to example B-5, synthesized by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can obtain according to the people's such as Weidmann United States Patent (USP) 6,093,730,10/1998) and 2-methoxyl group-ethamine; MS-(-)-ion: M-1=337.1.
Example B-12
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides
Be similar to example B-4, (can be according to the people's such as Weidmann United States Patent (USP) 6,093 by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester, 730,10/1998 obtain) and N, N-dimethyl-ethyl-1, the 2-diamines synthesizes, and then is similar to example B-1f) carry out deprotection; MS-(+)-ion: M+1=352.1.
Example B-13
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides
Be similar to example B-5, synthesized by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can obtain according to the people's such as Weidmann United States Patent (USP) 6,093,730,10/1998) and 2-amino-ethanol; MS-(-)-ion: M-1=323.2.
Example C-1
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides
By 0.035gm1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 0.088g2-amino-propyl-1, the 3-glycol is dissolved in 1ml ethanol and refluxes this mixture 24h.Concentrated reaction mixture also is dissolved in resistates in the 10ml ethyl acetate.With 5ml1M HCl and water extraction ethyl acetate solution, dry (sodium sulfate) is also concentrated to produce the 0.042g white solid: MS-(+)-ion: 355.1.
Example C-2
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides
Be similar to example C-1, by 1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 2-amino-propyl-1, prepared by the 3-glycol: MS-(-)-ion: 353.2.
Example C-3
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides
Be similar to example C-1, by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 2-amino-propyl-1, prepared by the 3-glycol: MS-(-)-ion: 295.2.
Example D-1
[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-phenyl sulfenyl-phthalic acid
The mixture 3.5 days of 5.06g4-phenyl sulfenyl-phthalonitrile (21.4mmol), the 10ml50%KOH aqueous solution and 10ml methyl alcohol under agitation refluxes.Then with this mixture of dilution of 100ml water, also use the concentrated hydrochloric acid acidifying.The suction filtration precipitated product, water thoroughly cleans also in a vacuum in 60 ℃ of dryings.Obtain the 5.75g title compound; MS-(-)-ion: M-1=273.0.
B) (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-acetic acid
In mortar, 5.62g4-phenyl sulfenyl-phthalic acid (20.5mmol) and 1.55g glycine (20.5mmol) are thoroughly ground together.Then in oil bath, this mixture is heated to 210 ℃ to 220 ℃.Stir molten mass 15min with scraper at this temperature, then it is cooled to envrionment temperature in a vacuum.Obtain the 6.30g title compound; MS-(-)-ion: M-1=311.8.
C) (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
Under agitation by the mixture backflow 18h of 20ml methyl alcohol, 6.27g (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-acetic acid (20mmol) and the 0.3ml vitriol oil.Then add the dense sodium bicarbonate aqueous solution of 100ml and extract this mixture by the 100ml ethyl acetate.Via MgSO 4dry organic phase evaporation in a vacuum.Obtain the 6.54g title compound; MS-(+)-ion: M+1=328.0.
D) Isosorbide-5-Nitrae-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (B)
Under agitation 0.92g sodium (40mmol) is dissolved in the 100ml propyl carbinol.Then temperature is increased to 95 ℃ to 100 ℃, add 6.5g (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate (19.85mmol) is dissolved in the hot solution in the 20ml propyl carbinol and continues to stir 1h under 95 ℃ to 100 ℃.Evaporating solvent in a vacuum, add the 25ml2N HCl aqueous solution and 100ml ethyl acetate this mixture of vigorous stirring 1h, then suction filtration subsequently.Water thoroughly clean filter cake and under vacuum in 60 ℃ of dryings to produce the 4.43g yellow solid.Use methylene dichloride on silica gel by flash column chromatography: ethyl acetate (98:2) wash-out separates this A of 4.4g and the mixture of B.Evaporate the first elution fraction and obtain 1.99g A; 1h NMR (CDCl 3): δ=10.48 (bs, 1H), 8.39 (bs, 1H), 8.24 (d, 1H), (8.01 d, 1H), 7.35-7.55 (m, 6H), 4.39 (t, 2H), (1.77 m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).Evaporate the second elution fraction and obtain 2.26g B; 1h NMR (CDC1 3): δ=10.38 (bs, 1H), 8.32 (bs, 1H), 8.24 (d, 1H), (7.86 d, 1H), 7.37-7.56 (m, 6H), 4.39 (t, 2H), (1.77 m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).
E) the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
By 1.108g1,4-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (3mmol) is added in the solution that 4.59g bromine phosphorus oxide (16mmol) is dissolved in the 25ml anhydrous acetonitrile and by this mixture gentle reflux 1h under agitation.Then add 5.04g sodium bicarbonate (60mmol), then dropwise add 8ml water.After stirring 90min at ambient temperature, mixture is concentrated into to approximately 1/3rd of its volume in a vacuum, adds 40ml water and extract this mixture by the 30ml ethyl acetate.This mixture of suction filtration.Separate organic phase, via MgSO 4drying is also filtered by silicagel pad.Evaporate in a vacuum and produce the .885g title compound; 1h NMR (CDCl 3): δ=11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40-7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H) .98 (t, 3H).
F) 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
The bromo-4-hydroxyl of the 432mg1-that under agitation refluxes-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (1mmol), 63mg red phosphorus (2mmol), the aqueous solution (3mmol) of 0.4ml57 % by weight HI and the mixture 30min of 1ml Glacial acetic acid.Then, with 25ml ethyl acetate diluted reaction mixture, by the Celite pad suction filtration, use 0.2g NaHSO 3the solution that is dissolved in 5ml water cleans and uses the dense sodium bicarbonate aqueous solution of 5ml to clean twice.Via MgSO 4dry organic phase evaporation in a vacuum.Use hexane on silica gel by flash column chromatography: ethyl acetate (85:15) wash-out carrys out the purifying resistates.Obtain the 123mg title compound; 1h NMR (CDC1 3): δ=11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38-7.63 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H) .98 (t, 3H).
G) [(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Under agitation by the mixture backflow 24h of methyl alcohol (3.2mmol) solution of 113mg4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.32mmol), 244mg glycine (3.2mmol) and 6.4ml0.5N sodium methylate.Then evaporating solvent in a vacuum, be dissolved in resistates in 25ml water and clean by the 50ml ethyl acetate solution 2 times of gained.By adding concentrated hydrochloric acid, the pH value of this solution is adjusted into approximately to 3 and extract the slurries 2 times of gained by the 25ml ethyl acetate subsequently.Via MgSO 4the dry organic phase that merges is also evaporated in a vacuum.Obtain the 103mg title compound; 1h NMR (DMSO-d 6): δ=9.32 (t, 1H), 8.74 (s, 1H), 8.19 (d, 1H), 7.94 (d, 1H), 7.45-7.65 (m, 6H), 4.02 (d, 2H).
Example D-2
[(4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 1--6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), make to come from example D-1d) 1.447g compd B (4mmol) with the bromine phosphorus oxide, react.Carry out purification of crude product with the methylene dichloride wash-out by flash column chromatography on silica gel.Obtain the 0.985g title compound by evaporating the first elution fraction; 1h NMR (CDCl 3): δ=11.77 (s, 1H), 8.08 (d, 1H), 8.05 (s, 1H), 7.41-7.56 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
B) 4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1f), the bromo-4-hydroxyl of 540mg1--6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (1.25mmol) is reacted with red phosphorus and HI.Use hexane on silica gel by flash column chromatography: ethyl acetate (85:15) wash-out carrys out the purification of crude product.Obtain the 150mg title compound; 1h NMR (CDC1 3): δ=11.78 (s, 1H), 8.71 (d, 1H), 8.11 (t, 1H), 7.79 (d, 1H), 7.39-7.54 (m, 6H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
C) [(4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), 127mg4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.36mmol) is reacted with glycine and sodium methylate.Obtain the 118mg title compound; 1h NMR (DMSO-d 6): δ=9.33 (t, 1H), 8.80 (s, 1H), 8.11 (d, 1H), 7.79 (s, 1H), 7.49-7.65 (m, 6H), 4.01 (d, 2H).
Example D-3
[(1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A.1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation will be from example D-1d) 554mg compd A (1.5mmol) and the mixture gentle reflux 30min of 5ml phosphorus oxychloride.Then evaporate in a vacuum the excess chlorine phosphorus oxide and resistates is dissolved in the 15ml acetonitrile.Add 2.94g sodium bicarbonate (35mmol), then dropwise add 4ml water.After stirring 1h, mixture is concentrated into to approximately 1/3rd of its volume in a vacuum, adds 20ml water and extract this mixture 2 times by the 20ml ethyl acetate.Via MgSO 4the dry organic phase that merges is also by the silicagel pad suction filtration.Evaporate in a vacuum and produce the 426mg title compound; 1h NMR (CDCl 3): δ=11.85 (s, 1H), 8.23 (d, 1H), 7.95 (d, 1H), 7.50-7.57 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
B) [(1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), 194mg1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) is reacted with glycine and sodium methylate.Obtain the 168mg title compound; 1h NMR (DMSO-d 6): δ=9.17 (t, 1H), 8.24 (d, 1H), 7.51-7.79 (m, 7H), 4.00 (d, 2H).
Example D-4
[(1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-3a), make to come from example D-1d) 554mg compd B (1.5mmol) with phosphorus oxychloride, react.Carry out purification of crude product with the methylene dichloride wash-out by flash column chromatography on silica gel.Obtain the 205mg title compound by evaporating the first elution fraction; 1h NMR (CDCl 3): δ=11.78 (s, 1H), 8.08 (d, 1H), 8.06 (s, 1H), 7.41-7.56 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
B) [(1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), 194mg1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) is reacted with glycine and sodium methylate.Obtain the 155mg title compound; 1h NMR (DMSO-d 6): δ=9.19 (t, 1H), 8.18 (d, 1H), 7.52-7.79 (m, 7H), 4.00 (d, 2H).
Example D-5
[(the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), make to come from example D-1e) the bromo-4-hydroxyl of 216mg1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) with glycine and sodium methylate, react.Obtain the 192mg title compound; 1h NMR (DMSO-d 6): δ=9.15 (t, 1H), 8.22 (d, 1H), 7.52-7.74 (m, 7H), 4.01 (d, 2H).
Example D-6
[(the bromo-4-hydroxyl of 1--6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), make to come from example D-2a) the bromo-4-hydroxyl of 216mg1--6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) with glycine and sodium methylate, react.
Obtain the 194mg title compound; 1h NMR (DMSO-d 6): δ=9.17 (t, 1H), 8.12 (d, 1H), 7.51-7.78 (m, 7H), 4.00 (d, 2H).
Example D-7
[(4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-phenoxy group-phthalic acid
Be similar to example D-1a) synthetic by 4-phenoxy group-phthalonitrile; MS-(-)-ion: M-1=256.9.
B) (1,3-dioxy-5-phenoxy group-1,3-dihydro-isoindole-2-yl)-acetic acid
Be similar to example D-1b) synthetic by 4-phenoxy group-phthalic acid; MS-(+)-ion: M+1=297.9.
C) (1,3-dioxy-5-phenoxy group-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to example D-1c) by (1,3-dioxy-5-phenoxy group-1,3-dihydro-isoindole-2-yl)-acetic acid synthetic (use hexane on silica gel by flash column chromatography: ethyl acetate (1:1) wash-out carrys out the purification of crude product); 1h NMR (CDC1 3): δ=7.83 (d, 1H), 7.05-7.46 (m, 7H), 4.41 (s, 2H), 3.76 (s, 3H).
D) Isosorbide-5-Nitrae-dihydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to example D-1d} synthetic by (1,3-dioxy-5-phenoxy group-1,3-dihydro-isoindole-2-yl)-methyl acetate; A: 1h NMR (CDCl 3): δ=10.58 (bs, 1H), 8.37 (bs, 1H), 8.14 (d, 1H), (7.87 d, 1H), 7.05-7.49 (m, 6H), 4.39 (t, 2H), (1.77 m, 2H), 1.46 (m, 2H), 0.99 (t, 3H); B: δ=10.38 (bs, 1H), 8.38 (d, 1H), 8.28 (bs, 1H), 7.56 (d, 1H), 7.06-7.47 (m, 6H), 4.40 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).
E) the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), by l, 4-dihydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1h NMR (CDCl 3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08-7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
F) 4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Stir the mixture 15h of the bromo-4-hydroxyl of 208mg1--7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (0.5mmol), 49mg sodium acetate (0.6mmol), 50mg10 % by weight palladium charcoal, 10ml methyl alcohol and 5ml ethyl acetate in 1atm under hydrogen.Then by this mixture of Celite pad suction filtration concentrated in a vacuum.Make to divide between the resistates bicarbonate aqueous solution concentrated at 2ml half and 8ml ethyl acetate molten.Via MgSO 4dry organic phase.Evaporate in a vacuum and produce the 130mg title compound; 1h NMR (CDCl 3): δ=11.89 (bs, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10-7.53 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
G) [(4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester; 1h NMR (DMSO-d 6): δ=9.29 (t, 1H), 8.75 (s, 1H), 8.28 (d, 1H), 7.18-7.63 (m, 6H), 4.01 (d, 2H)
Perhaps, title compound is prepared as follows:
A') the bromo-2-methyl-ethyl benzoate of 4-
The bromo-2-tolyl acid of 25.3g4-and the 5ml vitriol oil are added in 425ml ethanol.Under reflux temperature, this compound of heating is 3 days.This solution is cooled to room temperature, is adjusted into neutral pH by adding sodium bicarbonate, and under reduced pressure is concentrated into about 100ml volume.The mixture that volume is reduced is minute molten between ethyl acetate and water, and cleans successively organic phase with saturated bicarbonate and salt brine solution.Via organic part of anhydrous sodium sulfate drying, and be concentrated into 28.2g clarified liq product; 1h NMR (200MHz, CDC1 3) δ 7.78-7.73 (d, J=8.2Hz, 1H), 7.38-7.32 (m, 2H), 4.40-4.28 (q, J=7Hz, 2H), 2.57 (s, 3H), 1.42-1.35 (t, J=7Hz, 3H).
B') 2-methyl-4-phenoxy group-ethyl benzoate
The bromo-2-methyl-ethyl benzoate of 27.5g4-is dissolved in the 120ml dry toluene.By 21.3g phenol, 73.6gCs 2cO 3, the active 4A molecular sieve of 551 μ L ethyl acetate, 22g and 5.68g90% copper trifluoromethanesulfcomposite (I) benzene complex add so far in solution.Reaction is placed under nitrogen atmosphere and under reflux temperature and heats 48h.The mixture of gained is minute molten between water and ethyl acetate, and remove insoluble material by meticulous sintered glass filter filtering mixt.With 1.0N NaOH, organic part is cleaned 3 times, clean 1 time with salt solution, via anhydrous sodium sulfate drying and be concentrated into 18.2g sundown liquid: 1h NMR (200MHz, CDCl 3) δ 7.93-7.88 (dd, J=1.3,7.8Hz, 1H) 7.39-7.30 (m, 2H), 7.19-7.10 (tt, J=1.2,7.4Hz, 1H), 7.06-7.7.0 (m, 2H), 6.80-6.75 (m, 2H), 4.37-4.26 (q, J=7.0Hz, 2H), 2.56 (s, 3H), (1.40-1.33 t, J=7.0Hz, 3H).
C') 2-{[(2,4-dimethoxy-benzyl)-oxyethyl group carbonyl methyl-amino]-methyl }-4-phenoxy group-ethyl benzoate
Prepare N-(2,4-dimethoxy-benzyl) glycine ethyl ester (people such as Ananthan S, " pharmaceutical chemistry magazine " be (1993) (J.Med.Chem.), the 36 (4), the 479-490 page) according to the document program.13.0g2-methyl-4-phenoxy group-ethyl benzoate is dissolved in the 102mL tetracol phenixin.9.05g N-bromine succinic diamide and 492mg benzoyl peroxide are added so far in solution.Heat this mixture 18h under nitrogen atmosphere, be cooled to room temperature, and filter to remove all insoluble substances by silicagel pad under reflux temperature.The solution of gained is concentrated into to slightly oil of 16.5g.
The above-mentioned thick oil of 2.0g is dissolved in the 10ml dry DMF.1.0g N-(2,4-dimethoxy-benzyl) glycine ethyl ester and 552mg salt of wormwood are added so far in solution.Stirred reaction mixture 16h under nitrogen atmosphere.The gained mixture is injected to 80ml water and divides 3 extractions by the 50ml ethyl acetate.Clean successively and merge organic part with half saturated bicarbonate solution and salt solution.Organic part is evaporated to the oily resistates and is suspended in 50ml ether and 10ml hexane again.Solution is cooled to 0 ℃, and filtration removes micro-insoluble substance.The dioxane solution of 4M HCl slowly is added in cold solution and is settled out solid matter.By solid collected by filtration salt and with cold diethyl ether, clean 2 times.Then by dividing molten by its dissolving between 150ml ethyl acetate and 100ml sodium bicarbonate aqueous solution by this solid.Separate organicly part, clean with salt solution, via anhydrous sodium sulfate drying and concentrate to provide 1.8g brown color oil; MS (+) m/z508.13 (m+1).
D') 2-(2,4-dimethoxy-benzyl)-4-hydroxyl-7-phenoxy group-1,2-dihydro-isoquinoline-3-carboxylic acid ethyl ester
Under nitrogen atmosphere by 460mg2-{[(2,4-dimethoxy-benzyl)-oxyethyl group carbonyl methyl-amino]-methyl-4-phenoxy group-ethyl benzoate is dissolved in the anhydrous THF of 16ml and by gained solution and is cooled to-78 ℃.Two (three silyls) Lithamides in 1.95mL 1.0M THF are added so far in solution.At-78 ℃ of reaction stirred 1.5h, and at room temperature stir 4.5 hours.Gained solution is injected to saturated aqueous ammonium chloride and is extracted with ethyl acetate 3 times.Clean organic part with salt solution, via anhydrous sodium sulfate drying and be concentrated into yellow oil.With the 20-75% ethyl acetate gradient elution in hexane, make this oil quick post of crossing on silica gel.Under reduced pressure elution fraction is concentrated into to the 373mg yellow oil, it is enol and the ketone tautomers mixture of wanted product after measured; MS (+) m/z484.20 (m+23).
E') 4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid ethyl ester
By 365mg2-(2,4-dimethoxy-benzyl)-4-hydroxyl-7-phenoxy group-1,2-dihydro-isoquinoline-3-carboxylic acid ethyl ester is dissolved in the 7.9ml methylene dichloride.92 μ L thionyl chloride are added so far in solution.Reaction stirred 6.5h at room temperature, and then add 500 μ L ethanol reaction stirred 10min in addition.This mixture is divided between ethyl acetate and sodium bicarbonate molten.Clean successively organic part with 0.5M HCl, water, salt solution; Via anhydrous sodium sulfate drying, and be concentrated into the 468mg yellow oil.Carry out purifying this oil with the 15-50% ethyl acetate gradient elution in hexane by flash chromatography on silica gel, produce the 232mg crude product, the crystallization and produce 193mg creamy white solid from ether and hexane of this crude product; MS (+) m/z 310.08 (m+1).
F) [(4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Under the condition that is similar to example D1-g, by 4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid ethyl ester, prepare title compound.
Another alternative route of synthesis is for the following 4-hydroxyl provided-7-phenoxy group-isoquinoline-3-carboxylic acid ethyl ester.
A ") 2-bis-brooethyls-4-phenoxy group-ethyl benzoate
By the 40ml tetracol phenixin be added into be equipped with 2-methyl-4-phenoxy group-ethyl benzoate (example D-7b') (3.05g), in the flask of N-bromine succinic diamide (4.65g) and benzyl peroxide (115mg).At refluxed under nitrogen gained mixture 16h.Leach insolubles concentrated.Dilute this oil and filter by silicagel pad by 10% ethyl acetate in the 50ml hexane, further continuing to rinse 2 times by same solvent mixture.Concentrated 2-bis-brooethyls that are oily to produce 5g of solution-4-phenoxy group-ethyl benzoate will be leached. 1H NMR(200MHz,CDC1 3)δ8.07(s,1H),7.86(d,J=9Hz,1H),7.74(d,J=2.4Hz,1H),7.41(d,J=7.6,2H),7.21(m,1H),7.08(m,2H),6.86(dd,J=2.5,8.7,1H),4.37(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H)。
B ") 2-formyl radical-4-phenoxy group-ethyl benzoate
2-bis-brooethyls-4-phenoxy group-ethyl benzoate (2.07g) is dissolved in tetrahydrofuran (THF) (40ml) and water (15ml).Add Silver Nitrate (2.56g).The gained mixture is heated to reflux, continues 5h.Leach throw out and use ethyl acetate diluting reaction thing.Separate organic layer and again be extracted with ethyl acetate water layer.Clean the combined ethyl acetate layer and use dried over mgso with saturated sodium bicarbonate solution, salt solution.After concentrated, by 20% ethyl acetate in hexane (100ml), dilute thick oil and filter by silicagel pad.Continue further to rinse 2 times.The concentrated title compound that is oily to produce 1.13g of solution will be leached. 1H NMR(200MHz,CDCl 3)δ10.62(s,1H),7.98(d,J=8.6Hz,1H),7.42-7.35(m,3H),7.20-7.14(m,2H),7.04(d,J=8.2,2H),4.41(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H)。
C ") 2-(oxyethyl group carbonyl methyl-imino-methyl)-4-phenoxy group-ethyl benzoate
Anhydrous methylene chloride (2ml) is added in the dry flask that glycine ethyl ester hydrochloride (62mg) is housed, then adds triethylamine (124 μ L).Then adding sal epsom (uses fan heater predrying under high vacuum, 100mg), then adds methylene dichloride (1ml) solution of 2-formyl radical-4-phenoxy group-ethyl benzoate (120mg).The flask that 2-formyl radical-4-phenoxy group-ethyl benzoate is housed is further used to the 0.5ml dichloromethane rinse.The mixture 15h of stirring at room gained under nitrogen.Filter this mixture and use dichloromethane rinse.After removing solvent, with ether (15ml) diluting reaction thing and with salt solution, clean 2 times and drying.Filter and remove solvent, to produce 160mg, be the title compound that oily has good purity. 1H NMR(200MHz,CDC1 3)δ9.02(d,J=1.2,1H),7.94(d,J=8.6Hz,1H),7.63(d,J=2.4,1H),7.40-7.32(m,2H),7.20-7.11(m,1H),7.06-6.97(m,3H),4.41(s,2H),4.35(q,J=7.0Hz,2H),4.21(q,J=7.4Hz,2H),1.39(t,J=7.0Hz,3H),1.28(t,J=7.0Hz,3H)。
D ") 4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid ethyl ester
Make potassium tert.-butoxide (47mg) via high-vacuum pump in about 90 ℃ of dryings more than 1 hour.Under nitrogen, anhydrous tetrahydro furan (1.4ml) is added in potassium tert.-butoxide, then add tetrahydrofuran solution (1.6ml) solution of 2-(oxyethyl group carbonyl methyl-imino-methyl)-4-phenoxy group-ethyl benzoate (60mg), and further add the 0.5ml tetrahydrofuran (THF).Mixture becomes redness by safran.After at room temperature stirring 2.5h, by mixture reflux again 2.5h and then water (5ml) make its quenching.Add ethyl acetate (30ml).Separate organic phase and clean and drying with salt solution.Remove solvent and be to produce 26mg the title compound that oily has good purity. 1h NMR (200MHz, CDC1 3): with example D-7e') identical.
Example D-8
[(4-hydroxyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 1--6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), by coming from example D-7d) dihydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester synthetic; 1h NMR (CDCl 3): δ=11.76 (s, 1H), 8.22 (d, 1H), 7.68 (d, 1H), 7.10-7.55 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
B) 4-hydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-7f), synthetic by the bromo-4-hydroxyl of 1--6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester; 1h NMR (CDCl 3): δ=11.76 (s, 1H), 8.74 (s, 1H), 7.93 (d, 1H), 7.69 (d, 1H), 7.10-7.52 (m, 6H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
C) [(4-hydroxyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester; 1h NMR (DMSO-d 6): δ=9.33 (t, 1H), 8.82 (s, 1H), 8.23 (d, 1H), 7.20-7.63 (m, 7H), 4.01 (d, 2H).
Example D-9
[(1-chloro-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 1-chloro-4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-3a), by from example D-7d) l, 4-dihydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1h NMR (CDCl 3): δ=11.90 (s, 1H), 8.37 (d, 1H), 7.10-7.64 (m, 7H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
B) [(1-chloro-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 1-chloro-4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester; 1h NMR (DMSO-d 6): δ=9.16 (t, 1H), 8.36 (d, 1H), 7.23-7.72 (m, 7H), 4.01 (d, 2H).
Example D-10
[(1-chloro-4-hydroxyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 1-chloro-4-hydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-3a), by from example D-7d) l, 4-dihydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1h NMR (CDCl 3): δ=11.77 (s, 1H), 8.25 (d, 1H), 7.69 (d, 1H), 7.10-7.55 (m, 6H), 4.47 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
B) [(1-chloro-4-hydroxyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 1-chloro-4-hydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester; 1h NMR (DMSO-d 6): δ=9.19 (t, 1H), 8.31 (d, 1H), 7.23-7.74 (m, 7H), 4.00 (d, 2H).
Example D-11
[(the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), by from example D-7e) the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is synthetic; MS-(+)-ion: M+1=417.0.
Example D-12
[(the bromo-4-hydroxyl of 1--6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), by from example D-8a) the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is synthetic; MS-(-)-ion: M-1=414.9.
Example D-13
{ [7-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(2,6-dimethyl-phenoxy group)-phthalic acid
Be similar to example D-1a) synthetic by 4-(2,6-dimethyl-phenoxy group)-phthalonitrile; 1hNMR (CDC1 3): δ=7.89 (d, 1H), 7.19 (d, 1H), 7.08 (bs, 3H), 6.79 (m, lH), 2.10 (s, 6H).
B) [5-(2,6-dimethyl-phenoxy group)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
Be similar to example D-1b) make 4-(2,6-dimethyl-phenoxy group)-phthalic acid and glycine reactant.Then be similar to example D-1c), crude product is reacted with methyl alcohol; 1h NMR (CDC1 3): δ=7.80 (d, 1H), 7.09-7.17 (m, 5H), 4.40 (s, 2H), 3.76 (s .2H), 2.11 (s, 6H).
C) 7-(2,6-dimethyl-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation 0.79g sodium (34mmol) is dissolved in the 100ml propyl carbinol.Then temperature is increased to 95 ℃ to 100 ℃, disposable interpolation 5.70g[5-(2,6-dimethyl-phenoxy group)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate (16.8mmol) continuation stirring 3h under 95 ℃ to 100 ℃.Evaporating solvent in a vacuum, add the 25ml 2N HCl aqueous solution and 100ml ethyl acetate this mixture of vigorous stirring 30min, then suction filtration subsequently.Organic phase is separated from filtrate, via MgSO 4drying is also evaporated in a vacuum to produce brown size and is used the methyl alcohol wet-milling.By the throw out suction filtration of gained dry to produce the micro-yellow solid of 870mg (A) in a vacuum.Evaporate in a vacuum filtrate, be dissolved in a small amount of methyl alcohol and store whole night in refrigerator.By the throw out suction filtration of gained dry to produce the micro-yellow solid of 246mg (B) in a vacuum.Merge A and B and use methylene dichloride by flash column chromatography on silica gel: ethyl acetate (98:2) wash-out carries out purifying.Evaporate the first elution fraction and obtain the 762mg title compound; 1h NMR (CDC1 3): δ=8.31 (bs, 1H), 8.12 (d, 1H), 7.60 (d, 1H), 7.35 (m, 1H), 7.09 (bs, 3H), 4.39 (t, 2H), 2.11 (s, 6H), (1.77 m, 2H), 1.44 (m, 2H), 0.99 (t, 3H).
D) the bromo-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), synthetic by 7-(2,6-dimethyl-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester; 1h NMR (CDCl 3): δ=11.88 (s, 1H), 8.33 (m, 1H), 7.35-7.40 (m, 2H), (7.13-7.16 m, 3H), 4.46 (t, 2H), 2.14 (s, 6H), (1.83 m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
E) 7-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-7f), synthetic by the bromo-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; 1h NMR (CDCl 3): δ=11.87 (s, 1H), 8.35 (s, 1H), (8.36 d, 1H), 7.47 (dd, 1H), (7.14 m, 2H), 6.87 (d, 1H), (4.48 t, 2H), 2.14 (s, 6H), (1.87 m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
F) { [7-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 7-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=367.1.
Example D-14
{ [the chloro-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) the chloro-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-3a), by from example D-13c) 7-(2,6-dimethyl-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1h NMR (CDCl 3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.34-7.43 (m, 2H), (7.13-7.14 m, 3H), 4.47 (t, 2H), 2.14 (s, 6H), (1.85 m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
B) { [the chloro-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by the chloro-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=398.9.
Example D-15
{ [the bromo-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), by from example D-13d) the bromo-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; MS-(-)-ion: M-1=442.9.
Example D-16
[(the bromo-7-chloro-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
A) (5-chloro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetic acid
Be similar to example D-1b) come synthetic (use 5-chloro-isobenzofuran-1, the 3-diketone replaces corresponding phthalic acid as initial substance); 1h NMR (DMSO-d 6/ D 2o): δ=8.01 (s, 1H), 7.93 (s, 2H), 4.32 (s, 2H).
B) (5-chloro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to example D-1c) synthetic by (5-chloro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetic acid; 1h NMR (CDC1 3): δ=7.67-7.86 (m, 3H), 4.43 (s, 2H), 3.76 (s, 3H).
C) the chloro-Isosorbide-5-Nitrae-dihydroxyl of 7--isoquinoline-3-carboxylic acid butyl ester (A) and the chloro-Isosorbide-5-Nitrae-dihydroxyl of 6--isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to example D-1d), by (5-chloro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate synthetic (pure B by after chromatography from chloroform recrystallize obtain); A: 1h NMR (CDCl 3): δ=8.46 (bs, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.73 (dd, 1H), 4.41 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H); B: 1h NMR (CDCl 3): δ=8.34-8.38 (m, 2H), 8.12 (d, 1H), 7.64 (dd, 1H), 4.42 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H).
D) the bromo-7-chloro-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), synthetic by the chloro-Isosorbide-5-Nitrae-dihydroxyl of 7--isoquinoline-3-carboxylic acid butyl ester; 1h NMR (CDCl 3): δ=11.92 (s, 1H), 8.34 (d, 1H), 8.25 (d, 1H), 7.75 (dd, 1H), 4.49 (t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 1.00 (t, 3H).
E) [(the bromo-7-chloro-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by the bromo-7-chloro-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=356.8.
Example D-17
[(the bromo-6-chloro-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
A) the bromo-6-chloro-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), by from example D-16c) the chloro-Isosorbide-5-Nitrae-dihydroxyl of 6--the isoquinoline-3-carboxylic acid butyl ester is synthetic; 1h NMR (CDCl 3): δ=11.88 (s, 1H), 8.37 (d, 1H), 8.19 (d, 1H), 7.75 (dd, 1H), 4.49 (t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
B) [(the bromo-6-chloro-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by the bromo-6-chloro-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=356.9.
Example D-18
[(the bromo-4-hydroxyl of 1--7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) (1,3-dioxy-5-Trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to example D-1b) make 4-trifluoromethyl-phthalic acid and glycine reactant.Then be similar to example D-1c), crude product is reacted with methyl alcohol; 1h NMR (CDC1 3): δ=8.14 (s, 1H), 8.02 (m, 2H), 4.48 (s, 2H), 3.78 (s, 3H).
B) Isosorbide-5-Nitrae-dihydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester (A) and Isosorbide-5-Nitrae-dihydroxyl-6-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to example D-1d) synthetic by (1,3-dioxy-5-Trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methyl acetate; A: 1h NMR (CDCl 3): δ=10.47 (bs, 1H), 8.76 (bs, 1H), 8.72 (d, 1H), 8.29 (m, 1H), 7.99 (m, 1H), 4.45 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H); B: 1h NMR (CDCl 3): δ=10.48 (bs, 1H), 8.44-8.57 (m, 3H), 7.91 (d, 1H), 4.44 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.01 (t, 3H).
C) the bromo-4-hydroxyl of 1--7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), synthetic by Isosorbide-5-Nitrae-dihydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester; 1h NMR (CDCl 3): δ 11.96 (s, 1H), 8.52-8.56 (m, 2H), 7.99 (dd, 1H), 4.51 (t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 1.00 (t, 3H).
D) [(the bromo-4-hydroxyl of 1--7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by the bromo-4-hydroxyl of 1--7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=391.0.
Example D-19
[(the bromo-4-hydroxyl of 1--6-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 1--6-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), by from example D-18b) Isosorbide-5-Nitrae-dihydroxyl-6-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; MS-(-)-ion: M-1=390.3.
B) [(the bromo-4-hydroxyl of 1--6-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by the bromo-4-hydroxyl of 1--6-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=390.9.
Example D-20
[(4-hydroxyl-1-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to example D-1c) synthetic by (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetic acid; 1h NMR (CDC1 3): δ=7.84-7.91 (m, 2H), 7.71-7.77 (m, 2H), 4.45 (s, 2H), 3.77 (s, 3H).
B.1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d), by (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate synthetic (before adding hydrochloric acid not evaporating solvent, do not add ethyl acetate); 1hNMR (DMSO-d 6): δ=10.66 (bs, 1H), 10.55 (bs, 1H), 8.27 (d, 1H), (8.08 d, 1H), 7.72-7.92 (m, 2H), 4.33 (t, 2H), (1.74 m, 2H), 1.44 (m, 2H), 0.93 (t, 3H).
C.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-3a), by l, 4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1h NMR (CDCl 3): δ=11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
D) 4-hydroxyl-1-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
The mixture of 1.399g1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (5mmol) and 2.86g phenol is heated to 24h at 145 ℃ to 150 ℃.After being cooled to envrionment temperature, mixture is suspended in the 50ml 2N NaOH aqueous solution and extracts this mixture by 4 * 25ml ethyl acetate.Clean and merge organic phase with 3 * 25ml 2N NaOH aqueous solution, 50ml salt solution, via MgSO 4dry also evaporation in a vacuum.Use hexane on silica gel by flash column chromatography: ethyl acetate (9:1) and (95:5) wash-out carry out the purifying resistates.Obtain the 0.650g title compound; 1h NMR (CDC1 3): δ=11.52 (s, 1H), 8.32-8.39 (m, 2H), 7.72-7.86 (m, 2H), 7.13-7.42 (m, 5H), 4.31 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H).
E) [(4-hydroxyl-1-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-phenoxy group-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=339.1.
Example D-21
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 1,7-bis--3-carbonyl)-amino]-acetic acid
A) (5-bromo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate
Bromine phthalic imidine (35g, 155mmol) and bromoethyl acetate (bromoethylacetate) (31g, 186mmol) are dissolved in 700ml acetone.Add salt of wormwood (64.2g, 465mmol) and stir the suspension 18h of gained under refluxing.After cooling, filter this mixture.The evaporation filtrate is to produce 48.12g (154mmol) solid product. 1HNMR(200MHz,CDCl 3)δ8.00(s,1H),7.89(d,J=7.8Hz,1H),7.73(d,J=7.8Hz,1H),4.41(s,2H),4.21(q,J=7.0Hz,2H),1.28(t,J=7.0Hz,3H)。
B) the bromo-Isosorbide-5-Nitrae-dihydroxyl of 6-and 7--isoquinoline-3-carboxylic acid butyl ester
During under heating, (45-50 ℃) is dissolved in the 460ml propyl carbinol by sodium (10.45g).Above-mentioned ester (68g, 218mmol) is dissolved in the 460ml propyl carbinol and (is heated to evenly), and then be added in sodium solution.At 75 ℃ of lower mechanical stirring combined mixture 1h.Remove mixture stirred overnight at room temperature by heating.Use 2N HCl that solution is acidified to pH and be about 3.Then by washed with methanol, to produce 59.4g (175mmol), be the product of two kinds of isomer mixtures by vacuum filtration collecting precipitation thing water.
C) the bromo-Isosorbide-5-Nitrae-dihydroxyl of 7--isoquinoline-3-carboxylic acid butyl ester
Carry out the flash chromatography on silica gel method, by the above-mentioned heterogeneous mixture of 10g with 10% eluent ethyl acetate in methylene dichloride to produce the be white in color product of solid of 3g.MS-(+)-ion: M+1=342.02,340.02.
D) 1, the bromo-4-hydroxyl of 7-bis--isoquinoline-3-carboxylic acid butyl ester
Above-mentioned ester (2.4g, 7.1mmol) is dissolved in the 150ml anhydrous acetonitrile.Add bromine phosphorus oxide (14.1g, 49.4mmol).3h stirs the mixture under refluxing.After cooling, concentrated reaction mixture also is placed in ethyl acetate by resistates.Under effectively stirring, ethyl acetate mixture is injected to saturated sodium bicarbonate solution.Separate two-phase.Merge organic layer, filtration concentrated to produce 2g product (5.0mmol) via dried over mgso.MS-(+)-ion: M+1=403.90.
E}[(1, the bromo-4-hydroxyl-isoquinoline 99.9 of 7-bis--3-carbonyl)-amino]-acetic acid
Above-mentioned ester (0.2g, 0.5mmol) is dissolved in 5ml ethanol.Glycine (0.24g, 9.9mmol) and sodium ethylate (0.34g, 5mmol) are added so far in solution.
Under refluxing, stir the mixture 3 days.Evaporating mixture.Resistates is dissolved in the water and cleans by ethyl acetate.Use 1N HCl acidified aqueous solution water layer to pH=3-4, then be extracted with ethyl acetate.Via the dried over mgso organic layer, filter and concentrate to produce the be white in color product of solid of 0.17g. 1H NMR(200MHz,DMSO-d6)δ9.26(t,J=6.2Hz,1H),8.32(d,J=1.6Hz,1H),8.23(d,J=9.0Hz,1H),8.11(dd,J=9.0,1.6Hz,1H),4.02(d,J=6.2Hz,2H)。
Example D-22
[(the bromo-1-chloro-4-hydroxyl-isoquinoline 99.9 of 7--3-carbonyl)-amino]-acetic acid
A) the bromo-1-chloro-4-hydroxyl of 7--isoquinoline-3-carboxylic acid butyl ester
Bromo-Isosorbide-5-Nitrae-the dihydroxyl of 170mg (0.5mmol) 7--isoquinoline-3-carboxylic acid butyl ester (from example D-21c) is dissolved in the 2ml anhydrous acetonitrile.Add phosphorus oxychloride (536mg, 3.5mmol) and stir the mixture 4h of gained under refluxing.After cooling, concentrated this mixture is also inserted resistates in ethyl acetate.Ethyl acetate mixture is injected to saturated sodium bicarbonate solution, effectively stir 1h simultaneously.Separate two-phase.Be extracted with ethyl acetate water layer.Merge organic layer, filtration concentrated via dried over mgso.By silica gel chromatography, use the methylene dichloride wash-out to come the purification of crude product to produce the be white in color product of solid of 78mg.MS-(+)-ion: M+1=359.96,357.98.
B) [(the bromo-1-chloro-4-hydroxyl-isoquinoline 99.9 of 7--3-carbonyl)-amino]-acetic acid
Be similar to example D-21e), make above-mentioned ester and glycine (341mg, 4.18mmol) and sodium ethylate (143mg, the 2.09mmol) reaction of 75mg (0.21mmol).Obtain the 58mg product. 1HNMR(200MHz,CD 3OD)δ8.44(d,J=1.6Hz,1H),8.28(d,J=9.0Hz,1H),8.00(dd,J=9.0,1.6Hz,1H),4.17(s,2H)。
Example D-23
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 6--3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 6--isoquinoline-3-carboxylic acid butyl ester
2.58g (6.40mmol) 6-and the bromo-Isosorbide-5-Nitrae-dihydroxyl of 7--isoquinoline-3-carboxylic acid butyl ester mixture (from example D-21b) are dissolved in the 30ml Glacial acetic acid.Add palladium (10% in the activated carbon) slurries in the 10ml Glacial acetic acid.2h stirs the mixture under nitrogen atmosphere (storage pressure).Leach catalyzer and use dichloromethane rinse by Celite pad.Concentrating filtrate by resistates wet-milling in methylene dichloride.By filtering and using the silica gel chromatography of (3/1) hexane/ethyl acetate to collect insoluble solids to produce the 192mg product.MS-(-)-ion: M-1=324.11,322.13.
B) [(the bromo-4-hydroxyl-isoquinoline 99.9 of 6--3-carbonyl)-amino]-acetic acid
Be similar to example D-21e), make above-mentioned ester and glycine (1.23g, 16.43mmol) and sodium ethylate (746mg, the 10.96mmol) reaction of 178mg (0.55mmol).The product further obtained with the wet-milling of 30ml methyl alcohol produces the 58mg product. 1H NMR(200MHz,CD 3OD)δ8.72(s,1H),8.46(s,1H),7.98(d,J=8.8Hz),7.86(d,J=8.8Hz,lH),4.14(s,2H)。
Example D-24
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of the bromo-7-of 1--3-carbonyl)-amino]-acetic acid
A) (5-fluoro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
By 5-fluoro-isobenzofuran-1, the solid mixture of 3-diketone (3.68g, 22.15mmol) and glycine (1.66g, 22.15mmol) stirs 5min under 200-220 ℃.After cooling, it is dissolved in 25ml acetone.Add methyl-sulfate (4.19g, 33.23mmol) and salt of wormwood (4.59g, 33.23mmol).Stir this mixture 2h under refluxing.After cooling, it is diluted by the 100ml ethyl acetate.Leach insolubles concentrating filtrate.Resistates is placed in to 200ml ethyl acetate water and salt solution to be cleaned.Via dried over mgso ethyl acetate layer, filtration concentrated to produce the 5.1g product. 1H NMR(200MHz,CDC1 3)δ7.88(dd,J=8.2,4.3Hz,1H),7.54(dd,J=6.8,2.2Hz,1H),7.40(m,1H),4.44(s,2H),3.77(s,3H)。
B) the fluoro-Isosorbide-5-Nitrae-dihydroxyl of 7--isoquinoline-3-carboxylic acid butyl ester (A) and the fluoro-Isosorbide-5-Nitrae-dihydroxyl of 6--isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to example D-21b, under 95-100 ℃, the above-mentioned ester of 3.0g (12.66mmol) reset to 2h, be the product of isomer mixture to produce 2.5g.By silica gel chromatography, use the 5-20% eluent ethyl acetate in methylene dichloride to carry out the purifying heterogeneous mixture.Concentrated the first elution fraction and from 60ml ethanol recrystallize to produce 268mg solid product (A).Concentrated the second elution fraction is to produce 313mg solid product (B).For product A: MS-(-)-ion: M-1=278.02; For product B: MS-(-)-ion: M-1=278.03.
Can on the silica gel tlc plate, by 10% ethyl acetate in methylene dichloride, measure the difference of isomer A and B: A:R fvalue is about 0.79; B:R fvalue is about 0.53.
C) the fluoro-4-hydroxyl of the bromo-7-of 1--isoquinoline-3-carboxylic acid butyl ester
Being similar to example D-21d (with 10% methyl alcohol in methylene dichloride, replacing ethyl acetate) comes the above-mentioned ester of bromination 250mg (0.90mmol) (A) to produce the 156mg solid product.MS-(+)-ion: M+1=344.00,341.99.
D) [(the fluoro-4-hydroxyl-isoquinoline 99.9 of the bromo-7-of 1--3-carbonyl)-amino]-acetic acid
Be similar to example D-21e, make the above-mentioned ester of 60mg (0.18mmol) and glycine reactant (reaction times is 48h).Extract this product with 10% methyl alcohol in methylene dichloride.Via dried over mgso organic layer, filtration concentrated to produce the 50mg product.MS-(-)-ion: M-1=343.02,340.92; 1h NMR (200MHz, acetone-d 6) δ 13.56 (s, 1H), 8.81 (br s, 1H), 8.43 (dd, J=9.0,5.4Hz, 1H), 7.79 (m, 2H), 4.29 (d, J=6.2Hz, 2H).
Example D-25
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of 7--3-carbonyl)-amino]-acetic acid
The above-mentioned carboxylic acid of 42mg (0.12mmol) is dissolved in 5ml (4/1) methanol/water.Add sodium carbonate (13mg, 0.12mmol) and palladium (wet, 10% dry matter on activated carbon) (40mg).2h stirs the mixture under nitrogen atmosphere (storage pressure).Leach catalyzer and also then rinse with 2ml water by 10ml (4/1) methanol/water by Celite pad.Concentrating filtrate is to remove most of methyl alcohol and to be acidified to pH=3-4 by 1N HCl.By filtration collecting precipitation thing dry to produce the 14mg product under high vacuum.MS-(-)-ion: M-1=262.99; 1h NMR (200MHz, CD 3oD) δ 8.69 (s, 1H), 8.38 (dd, J=9.0,5.5Hz, 1H), 7.24 (dd, J=9.3,2.4Hz, 1H), 7.60 (m, 1H), 4.14 (s, 2H).
Example D-26
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of the chloro-7-of 1--3-carbonyl)-amino]-acetic acid
A) the fluoro-4-hydroxyl of the chloro-7-of 1--isoquinoline-3-carboxylic acid butyl ester
Fluoro-Isosorbide-5-Nitrae-the dihydroxyl of 135mg (0.48mmol) 7--isoquinoline-3-carboxylic acid butyl ester (from the product A of example D-24b) is dissolved in the 3ml anhydrous acetonitrile.Add phosphorus oxychloride (1.24g, 8.07mmol).Stir this mixture 6h under refluxing.After cooling, it is concentrated and be suspended in the 10ml saturated sodium bicarbonate aqueous solution.Stir 1h and use 5% methanol extraction in methylene dichloride.Clean organic layer with salt solution, via dried over mgso, filtration concentrated.By silica gel chromatography, use the methylene dichloride wash-out to come the purification of crude resistates to produce the 58mg product.MS-(-)-ion: M-1=296.12.
The fluoro-4-hydroxyl-isoquinoline 99.9 of the chloro-7-of b.[(1--3-carbonyl)-amino]-acetic acid
Be similar to example D-21e, make the above-mentioned ester of 55mg (0.19mmol) and glycine reactant.After acidifying, with 10% methanol extraction in methylene dichloride.Clean organic layer with salt solution, via dried over mgso, filtration concentrated.By the preparation TLC purifying resistates on 10% methyl alcohol in methylene dichloride to produce the 6mg product. 1h NMR (200MHz, acetone-d6) δ 13.59 (s, 1H), 8.90 (br s, 1H), 8.47 (dd, J=9.0,5.1Hz, 1H), 7.94 (dd, J=9.7,2.4Hz, 1H), 7.81 (m, 1H), 4.28 (d, J=6.2Hz, 2H).
Example D-27
[(chloro-4-hydroxyl-benzo [g] isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) (1,3-dioxy-1,3-dihydro-benzo [f] isoindole-2-yl)-ethyl acetate
Be similar to example D-21a, make 2g (10.1mmol) benzo [f] isoindole-1,3-diketone and ethyl bromoacetate reaction.Minute molten and obtain crude product between ethyl acetate and water.Clean organic layer with salt solution, via dried over mgso, filter and evaporate to produce 2.68g (9.5mmol) product. 1H NMR(200MHz,CDC1 3)δ8.36(s,2H),8.05(m,2H),7.68(m,2H),4.49(s,2H),4.22(q,J=7.0Hz,2H),1.29(t,7.0Hz,3H)。
B) Isosorbide-5-Nitrae-dihydroxyl-benzo [g] isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-21b, the above-mentioned isoindole ester of 2.6g (9.2mmol) is reset to produce 1.23g (3.9mmol) product. 1HNMR(200MHz,CDC1 3)δ10.73(br s,1H),9.00(s,1H),8.68(s,1H),8.24(br s,1H),8.06(m,2H),7.68(m,2H),4.24(t,J=6.6Hz,2H),1.80(m,2H),1.47(m,2H),1.00(t,J=7.4Hz,3H)。
C) 1-chloro-4-hydroxyl-benzo [g] isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-22a but with acetonitrile, as cosolvent, do not make the above-mentioned ester of 1g (3.2mmol) and 5ml phosphorus oxychloride react to produce 0.88g (2.7mmol) product. 1HNMR(200MHz,CDC1 3)δ12.24(s,1H),8.97(s,1H),8.85(s,1H),8.12(m,2H),7.70(m,2H),4.51(t,J=7.0Hz,2H),1.89(m,2H),1.56(m,2H),1.00(t,J=7.2Hz,3H)。
D) [(chloro-4-hydroxyl-benzo [g] isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-21e, make the above-mentioned ester of 0.88g (2.7mmol) and glycine reactant.Collect the gained throw out by filtration after acidifying and dry to produce 0.30g (0.9mmol) product in high vacuum. 1H NMR(200MHz,DMSO-d6)δ9.34(br s,1H),9.00(s,1H),8.92(s,1H),8.34(m,2H),7.74(m,2H),3.94(d,J=5.4Hz,2H)。
Example D-28
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester
2g (7.7mmol) Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (from example D-20b) is dissolved in the 100ml acetonitrile.By 15.4g (53.6mmol) bromine phosphorus oxide, be added in solution and at 80 ℃ of 64h that stir the mixture.100ml water is added into to mixture and makes mixture leave thermal source.Mixture is divided between ethyl acetate and water molten.Separate two-phase and be extracted with ethyl acetate water layer.Merge organic layer, with salt solution clean, via dried over mgso, filtration evaporation.By flash chromatography on silica gel method purifying resistates to produce 0.1g (0.3mmol) product. 1H NMR(200MHz,CDCl 3)δ11.89(s,1H),8.41(m,1H),8.25(m,1H),7.84(m,2H),4.49(t,J=7.0Hz,2H),1.87(m,2H),1.47(m,2H),1.00(t,J=7.2Hz,3H)。
B) [(the bromo-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
Be similar to example D-21e, by the above-mentioned isoquinoline 99.9 ester of g (0.3mmol) and glycine reactant to produce the product of 0.08g (0.2mmol). 1H NMR(200MHz,CD 3OD)δ8.94(br s,1H),8.34(m,1H),8.24(m,1H),7.86(m,2H),4.18(d,J=6.2Hz,2H)。
Example D-29
[(4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
According to being similar to the program of describing in detail in example D-37, by [(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (example D-33), prepare title compound.Final product wants product to carry out purifying with 0 to 15% methyl alcohol in methylene dichloride and 0.5% acetic acid gradient elution by chromatography on silica gel; MS (-): m/z321.00 (M-1).
Example D-30
[(4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
According to being similar to the program of describing in detail in example D-37, by [(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (example D-34), prepare title compound.Final product wants product to carry out purifying with 0 to 15% methyl alcohol in methylene dichloride and 0.5% acetic acid gradient elution by chromatography on silica gel; MS (-): m/z321.02 (M-1).
Example D-31
[(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) (5-bromo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
50.3g4-bromine phthalic imidine, 92.0g salt of wormwood and 24.5ml methyl bromoacetate are added in 888ml acetone.The gained mixture is heated to reflux temperature, continues 24h, and then be cooled to room temperature.Filter this mixture by meticulous glass sintering filter and remove all solids material, and then concentrate the wanted product of this solution to provide 66g to be white in color solid under vacuum; 1h NMR (CDC1 3): δ=3.76 (s, 3H), 4.43 (s, 2H), 7.71-7.75 (m, lH), 7.85-7.90 (dd, 1H), 8.00 (m, 1H).
B) (1,3-dioxy-5-phenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
The above-mentioned bromine phthalic imidine of 6.0g product is dissolved in the 70ml glycol dimethyl ether.3.7g phenyl-boron dihydroxide, 13g cesium carbonate and 2g tetrakis triphenylphosphine palladium (0) are added so far in solution.Stir this mixture 48h in 65 ℃ under nitrogen atmosphere.The gained mixture is injected to 250ml semi-saturation sodium bicarbonate aqueous solution and then by the 200ml ethyl acetate, divides 3 extractions.Clean and merge organic part also then via dried over sodium sulfate with 200ml water, saturated sodium bicarbonate and salt brine solution successively.Solution is concentrated into to resistates (11g), and it wants product to carry out purifying with 0 to 25% ethyl acetate gradient elution in hexane by chromatography on silica gel.Obtain the 1.1g purified product; MS (+): m/z296.02 (M+1)
C) Isosorbide-5-Nitrae-dihydroxyl-7-phenyl-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenyl-isoquinoline-3-carboxylic acid butyl ester (B)
The above-mentioned product of 1.4g is added in the butanol solution of 18.8ml0.5N propyl carbinol sodium.The gained mixture is heated to 100 ℃, continues 2h, and then be cooled to room temperature.Mixture is injected to the 100ml0.5N aqueous hydrochloric acid and divides 3 extractions by the 100ml ethyl acetate.Filter and merge organic extract to remove any insoluble substance then water and salt solution cleaning successively.Via this solution of dried over sodium sulfate and be concentrated into resistates (1.1g) under vacuum, it carrys out purifying (R with 0 in methylene dichloride to two primary products of 20% ethyl acetate gradient elution by chromatography on silica gel fisomer A=0.64, R fb=0.48; 15% ethyl acetate: 85% methylene dichloride).
Isomer A:397mg; MS (+) m/z388.11 (M+1)
Isomer B:195mg; MS (+) m/z388.10 (M+1)
D) 1-chloro-4-hydroxyl-6-phenyl-isoquinoline-3-carboxylic acid butyl ester
Under the condition of describing in detail in being similar to example D-39d, use above-mentioned isomer B1,4-dihydroxyl-6-phenyl-isoquinoline-3-carboxylic acid butyl ester prepares title compound; MS (+): m/z356.06 (M+1)
E) [(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
The following title compound that obtains: the above-mentioned ester of 95mg and 300mg glycine are suspended in the methanol solution of 5.4ml0.5N sodium methylate.This mixture is heated to reflux temperature, continues 42h, and then be cooled to room temperature.With 30ml bicarbonate aqueous solution dilution mixture, also by the 30ml ethyl acetate, clean.Be 3 with the 6N aqueous hydrochloric acid by this acidified aqueous solution to pH value, and then by the 35ml ethyl acetate, divide 3 extractions.Merge organic extract and concentrated to produce the be white in color product of being wanted of solid of 73mg under vacuum via dried over sodium sulfate; MS (-): m/z354.99 (M-1).
Example D-32
[(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
According to being similar to the program of describing in detail in example D-39d and D-39e, by Isosorbide-5-Nitrae-dihydroxyl-7-phenyl-isoquinoline-3-carboxylic acid butyl ester (example D-33c isomer A), prepare title compound.
1-chloro-4-hydroxyl-7-phenyl-isoquinoline-3-carboxylic acid butyl ester; MS (+): m/z356.09 (M+1)
[(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid; MS (-): m/z355.01 (M-1)
Example D-33
[(the bromo-4-hydroxyl of 1--6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
By 161mg1,4-dihydroxyl-6-phenyl-isoquinoline-3-carboxylic acid butyl ester (example D-33c isomer B) is suspended in the 3ml anhydrous acetonitrile.Add 896mg bromine phosphorus oxide, and this mixture is heated to reflux temperature, continue 5h.Mixture is cooled to room temperature, be evaporated to resistates and be suspended in the 40ml ethyl acetate and the mixture of the 40ml sodium bicarbonate semi-saturation aqueous solution in.Stir rapidly two-phase mixture 10min, and then by the 40ml ethyl acetate, divide 3 extractions.Concentrate under vacuum and merge organic extract and carry out purifying with main part of the 0-5% ethyl acetate gradient elution in methylene dichloride by chromatography on silica gel.Reclaim the 26mg material and be directly used in next reaction.
Resistates and 58mg glycine are suspended in the methanol solution of 1.4ml0.5N sodium methylate.Mixture is heated to reflux, continues 18h, then be cooled to room temperature and be evaporated to about 0.5ml.Also with the 6N aqueous hydrochloric acid, being acidified to the pH value with 30ml water dilution mixture is 3.Collect the gained throw out and clean 2 times with cold water.Dried solid product under vacuum and obtain 16mg and want product; MS (-): m/z398.90,400.92 (M-1, M+1; The Br isotropic substance).
Example D-34
[(the bromo-4-hydroxyl of 1--7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Use is similar to the condition of describing in detail in example D-35, by Isosorbide-5-Nitrae-dihydroxyl-7-phenyl-isoquinoline-3-carboxylic acid butyl ester (example D-33c isomer A), prepares title compound.Final product wants product to carry out purifying with 0 to 10% methyl alcohol in methylene dichloride and 0.5% acetic acid gradient elution by chromatography on silica gel; MS (-): m/z398.91,400.95 (M-1, M+1; The Br isotropic substance).
Example D-35
[(4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Will be from the 200mg[(1-chloro-4-hydroxyl of example D-39e-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid is suspended in the solution of 12ml MeOH and 4ml water.This mixture 18h is provided under the nitrogen atmosphere of adding 45mg sodium carbonate and 100mg10 % by weight palladium/activated carbon and providing at the ball by being filled with hydrogen.With methyl alcohol and sodium bicarbonate aqueous solution dilution gained mixture, also then by Celite pad, filter.This solution of concentrating under reduced pressure, to about 6ml, then is diluted to 30ml with the semi-saturation bicarbonate solution, and then with concentrated hydrochloric acid aqueous solution, to be acidified to the pH value be 3.Divide extraction water solution 3 times by the 30ml ethyl acetate.Merge organic extract the wanted product of concentrating under reduced pressure to provide 107mg to be white in color solid via dried over sodium sulfate; MS (+): m/z323.08 (M+1).
Example D-36
[(4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Use is similar to the condition of describing in detail in example D-37, by [(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (example D-40), prepares title compound; MS (+): m/z323.06 (M+1).
Example D-37
[(1-chloro-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) xenyl-2, the 3-dioctyl phthalate
15g of 2-methyl-3-xenyl methyl alcohol and 75mg cetrimonium bromide are added in 150ml water, and in ice bath, the gained mixture are cooled to 0 ℃.Be added in cold mixt by 48g potassium permanganate and, at 0 ℃ of lower reaction stirred 10min, at room temperature stir 16h, then under 70 ℃, stirring 48h.Filter the settled solution that contains black solid by Celite pad, and clean with the 100ml methylene dichloride.With the 6N aqueous hydrochloric acid, by this acidified aqueous solution to pH value, be then 3, and then by the 150ml ethyl acetate, divide 4 extractions.Merge organic part via anhydrous sodium sulfate drying, and be concentrated into the 12.9g product; 1hNMR (d6-DMSO): δ=7.28-7.46 (m, 5H), 7.51-7.61 (m, 2H), 7.84-7.89 (dd, 1H), 13.0 (s, 2H).
B) (1,3-dioxy-4-phenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
With mortar, the above-mentioned diprotic acid of 10.5g and 3.25g glycine are mixed and grind and follow in the oil bath be held between 210 to 230 ℃ and heat 15min.Cooling this mixture also is directly used in next reaction by the gained solid.
The thick phthalic imidine product that 7.4g salt of wormwood and 5.7ml methyl-sulfate are added into from above-mentioned reaction is dissolved in the solution of 125ml acetone.This mixture is heated to reflux temperature, continues 24h, and then be cooled to room temperature.Clean this mixture and extract 3 times by the 500ml ethyl acetate with 500ml water.With organic part of salt solution cleaning merging and via dried over sodium sulfate.Concentrated this solution and by the gained solid from ethyl acetate crystallization to obtain the 5.0g light yellow solid; 1hNMR (CDC1 3): δ=3.74 (s, 3H), 4.40 (s, 2H), 7.91-7.43 (m, 8H).
C) Isosorbide-5-Nitrae-dihydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-5-phenyl-isoquinoline-3-carboxylic acid butyl ester (B)
The above-mentioned product of 5.07g is added in the butanol solution of 68.8ml0.5N propyl carbinol sodium.The gained mixture is heated to 95 ℃, continues 4h, and then be cooled to room temperature.Add 2.1ml acetic acid this mixture of concentrating under reduced pressure to about 15ml volume.Dilute crude product and be extracted with ethyl acetate 3 times with the semi-saturation sodium hydrogen carbonate solution.Water, then with salt solution, clean and merge organic part and via dried over sodium sulfate.Concentrated this solution also carrys out purifying resistates (5.3g) (R with 0 in methylene dichloride to two main parts of 25% ethyl acetate gradient elution by chromatography on silica gel fisomer A=0.68, R fb=0.52,15% ethyl acetate: 85% methylene dichloride):
Isomer A, 2.19g; MS (+) m/z338.15 (M+1)
Isomer B, 1.22g; MS (+) m/z388.04 (M+1)
D) 1-chloro-4-hydroxyl-5-phenyl-isoquinoline-3-carboxylic acid butyl ester
500mg is suspended in the 5ml phosphorus oxychloride and is heated to 100 ℃ from the isomer B of above-mentioned reaction, continue 1h.Reaction mixture, be evaporated to resistates and, then with 30ml water and the dilution of 30ml ethyl acetate, stir rapidly simultaneously.The pH of monitoring water also is adjusted to the pH value to be about 7 by adding sodium bicarbonate.Stir two-phase mixture 30min, and then with 30ml ethyl acetate extraction 3 times.Clean and merge organic part also then via dried over sodium sulfate with saturated sodium bicarbonate solution and salt solution.This solution of concentrating under reduced pressure, and carry out purifying resistates (494mg) with 5 in methylene dichloride to main part of 20% ethyl acetate gradient elution by chromatography on silica gel.Obtain the 442mg purified product; MS:(+) m/z355.99 (M+1).
E) [(1-chloro-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
The above-mentioned ester of 435mg and 1.0g glycine are suspended in the methanol solution of 24.4ml0.5N sodium methylate.Mixture is heated to reflux, continues 18h, then be cooled to room temperature and be evaporated to about 5ml.Also with the 1N aqueous hydrochloric acid, being acidified to the pH value with 50ml water dilution mixture is 3.Collect the gained throw out and clean 2 times with cold water.Dried solid product under vacuum and obtain the 414mg product; MS (+) m/z356.99 (M+1).
Example D-38
[(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Use is similar to the condition of describing in detail in example D-39d and D-39e, by Isosorbide-5-Nitrae-dihydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester (example D-39c isomer A), prepares title compound.
1-chloro-4-hydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester; MS (+): m/z356.05 (M+1)
[(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid; MS (+): m/z356.99 (M+1)
Example D-39
[(the bromo-4-hydroxyl of 1--5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 1--5-phenyl-isoquinoline-3-carboxylic acid butyl ester
Will be from the 411mg1 of example D-39c isomer B, 4-dihydroxyl-5-phenyl-isoquinoline-3-carboxylic acid butyl ester is suspended in the 15ml anhydrous acetonitrile.Add 2.0g bromine phosphorus oxide and reaction mixture is heated to reflux, continuing 3.5h.Reaction mixture also is injected in the saturated sodium bicarbonate aqueous solution of 75ml0 ℃.Stir this mixture 5min, and then by the 75ml ethyl acetate, divide 3 extractions.Clean and merge organic part with salt solution, via dried over sodium sulfate concentrating under reduced pressure.Carry out purifying resistates (434mg) with 0 in hexane to 25% ethyl acetate gradient elution as the product of main part by chromatography on silica gel.Obtain 480mg and want product; MS (+): m/z422.02 (M+23).
B) [(the bromo-4-hydroxyl of 1--5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
The following title compound that obtains: the above-mentioned ester of 200mg and 412mg glycine are suspended in the methanol solution of 10ml0.5N sodium methylate.Mixture is heated to reflux, continues 24h, then be cooled to room temperature and be evaporated to about 3ml.Also with the 1N aqueous hydrochloric acid, being acidified to the pH value with 50ml water dilution mixture is 3.Collect the gained throw out and clean 2 times with cold water.Dried solid product under vacuum and obtain the 188mg product; MS (-): m/z398.96,400.95 (M-1, M+1; The Br isotropic substance).
Example D-40
[(the bromo-4-hydroxyl of 1--8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Use is similar to the condition of describing in detail in example D-41, by Isosorbide-5-Nitrae-dihydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester (example D-39c isomer A), prepares title compound.
The bromo-4-hydroxyl of 1--8-phenyl-isoquinoline-3-carboxylic acid butyl ester; MS (+): m/z400.00,402.03 (M+1, M+3; The Br isotropic substance).
[(the bromo-4-hydroxyl of 1--8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid; MS (-): m/z398.95,400.98 (M-1, M+1; The Br isotropic substance)
Example D-41
[(1-ethyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 1-ethyl sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
By 52mg1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (example D-20c), be dissolved in the 2ml sulfur alcohol and in sealed tube in 70 ℃ the heating 24h, and 100 ℃ the heating 48h.Concentrate gained solution and carry out purifying resistates (54mg) with 0 in hexane to 20% ethyl acetate gradient elution product by chromatography on silica gel under vacuum.Obtain the 25mg product; MS (+): m/z306.06 (M+1)
B) [(1-ethyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Under the condition of describing in detail, with above-mentioned ester, obtain title compound in being similar to example D-39e; MS (-) m/z304.98 (M-1).
Example D-42
{ [4-hydroxyl-1-(4-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
1ml4-anisole mercaptan is added into to 100mg[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (United States Patent (USP) 6,093,730, be disclosed as N-((1-chloro-4-hydroxyl isoquinoline 99.9-3-yl) carbonyl) glycine) be dissolved in the solution in the 1ml DMF.Heat 72h by under in 120 to 130 ℃ of this solution in sealed tube.Then that solution is concentrated under vacuum.Carry out purifying gained resistates (76mg) with 0 in methylene dichloride to 15% methyl alcohol and 0.5% acetic acid gradient elution product by chromatography on silica gel.Obtain the 6mg product; MS (+) m/z385.05 (M+1)
Example D-43
[(the iodo-isoquinoline 99.9 of 1-chloro-4-hydroxyl-7--3-carbonyl)-amino]-acetic acid
A) (5-iodo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetic acid
Make the iodo-phthalic acid of 10g4-and 2.63g glycine closely mix and this mixture is heated to 200 ℃, continue 10min.After cooling, be extracted with ethyl acetate the solid reaction mixture, produce 6.40g brown color solid after concentrating: MS-(-)-ion, proton N MR (200MHz, methyl alcohol-d-4): δ 8.26-8.18 (m, 2H), 7.68-7.61 (m, 1H), 4.39 (s, 1H).
B) (5-iodo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
With the 2.7g methyl-sulfate in 25ml backflow acetone and 3.0g salt of wormwood esterification 6.4g example D-55a) formic acid product 3h.With ethyl acetate diluted reaction mixture, filtration concentrated.Resistates is dissolved in fresh ethyl and cleans (water, salt solution) organic layer and via dried over sodium sulfate.The ethyl acetate solution after filtration of concentrate drying produces the micro-yellow solid of 5.8g.Proton N MR (200MHz, chloroform-d): δ 8.24-8.20 (m, 1H), 8.14-8.06 (m, 1H), 7.62-7.56 (d, 1H), 4.40 (s, 2H), 3.75 (s, 3H).
C) the iodo-1-oxygen-1 of 4-hydroxyl-7-, the iodo-1-oxygen-1 of 2-dihydro-isoquinoline-3-butyl formate and 4-hydroxyl ~ 6-, 2-dihydro-isoquinoline-3-carboxylic acid butyl ester
Under nitrogen atmosphere in 65 ℃ of dissolving metals of the sodium by the fresh incision of 0.40g in the 22ml propyl carbinol.3.0g (5-iodo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-mixture of methyl acetate in the 22ml propyl carbinol is added in sodium butylate solution and by reaction mixture and is heated to 80 ℃, continue 2h.The reaction mixture cooling with the 100ml1M hcl acidifying produces solid sediment.By solid collected by filtration and by silica gel chromatography (elutriant: 19:1 methylene dichloride: ethyl acetate) separate and produce the iodo-1-oxygen-1 of 0.219g4-hydroxyl-7-, 2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(-)-ion, the iodo-1-oxygen-1 of M-1=386.0amu and 0.150g4-hydroxyl-6-, 2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(-)-ion, M-1=386.0amu.
D) the iodo-isoquinoline-3-carboxylic acid butyl ester of 1-chloro-4-hydroxyl-7-
At room temperature, by the iodo-1-oxygen-1 of 0.215g4-hydroxyl-7-, 2-dihydro-isoquinoline-3-carboxylic acid butyl ester is added into 5ml POCl 3in.By reflux 3h remove POCl under vacuum of mixture 3.Resistates is dissolved in ethyl acetate and with saturated sodium bicarbonate aqueous solution and cleans this solution, drying (MgSO 4), filter and concentrate to produce the 0.205g white solid: proton N MR (200MHz, chloroform-d) δ 11.91 (s, 1H), (8.67 m, 1H), 8.10 (m, 2H), 4.49 (t, J=7Hz, 2H), 1.95-1.75 (m, 2H), (1.60-1.39 m, 2H), 1.00 (t, J=7Hz, 3H).
E) [(the iodo-isoquinoline 99.9 of 1-chloro-4-hydroxyl-7--3-carbonyl)-amino]-acetic acid
By the iodo-isoquinoline-3-carboxylic acid butyl ester of 0.095g1-chloro-4-hydroxyl-7-, be added in the mixture of 0.263g glycine in the 4.7ml0.5M sodium methylate and this reaction mixture 18h that refluxes.Concentrated this mixture, be dissolved in the water resistates and use this solution of 1M hcl acidifying.Be extracted with ethyl acetate throw out water and clean organic layer, drying (MgSO 4), filter and concentrate to produce the 0.079g light yellow product: MS-(-)-ion, M-1=406.9amu,
Example D-44
[(the iodo-isoquinoline 99.9 of 1-chloro-4-hydroxyl-6--3-carbonyl)-amino]-acetic acid
A) the iodo-isoquinoline-3-carboxylic acid butyl ester of 1-chloro-4-hydroxyl-6-
Be similar to example D-43d), make the iodo-1-oxygen-1 of 0.150g4-hydroxyl-6-, 2-dihydro-isoquinoline-3-carboxylic acid butyl ester and 5ml POC1 3reaction is to provide the shallow white solid of 0.057g: proton N MR (200MHz, chloroform-d): δ 11.9 (s, 1H), 8.89 (m, 1H), 8.1 (m, 1H), (7.97 m, 1H), 4.5 (t, J=7Hz, 2H), 2.0-1.8 (m, 2H), 1.65-1.4 (m, 2H), (1.00 t, J=7Hz, 3H).
B) [(the iodo-isoquinoline 99.9 of 1-chloro-4-hydroxyl-6--3-carbonyl)-amino]-acetic acid
Be similar to example D-55e) condition under, make 0.053g come from example D-44a) butyl ester and the mixture reaction of 0.147g glycine in the methanol solution of 2.6ml0.5M sodium methylate produce the product that 0.047g is the creamy white solid: MS-(-)-ion, M-1=406.9amu.
Example D-45
[(the iodo-isoquinoline 99.9 of 4-hydroxyl-7--3-carbonyl)-amino]-acetic acid
A) the iodo-isoquinoline-3-carboxylic acid butyl ester of 4-hydroxyl-7-
By 0.100g from example D-43d) product be dissolved in the Glacial acetic acid that 1.5ml contains 0.015g red phosphorus and 56 microlitre hydroiodic acid HIs (d=1.701g/ml).Reaction mixture refluxed 1h, dilute and filter by plug of celite by ethyl acetate.Clean filtrate, drying (MgSO with saturated aqueous sodium thiosulfate and saturated sodium bicarbonate aqueous solution 4), filter and concentrate to produce crude product.Crude product is used to silica gel chromatography (elutriant: 99:1CH 2cl 2-ethyl acetate) produce the 0.073g white solid.Proton N MR (200MHz, chloroform-d): δ 11.9 (s, 1H), 8.70 (s, 1H), 8.40-8.30 (m, 1H), 8.12-8.05 (m, 1H), 8.05-7.96 (m, 1H), 4.48 (t, J=7Hz, 2H), 1.95-1.80 (m, 2H), 1.60-1.40 (m, 2H), (0.99 t, J=7Hz, 3H).
B) [(the iodo-isoquinoline 99.9 of 4-hydroxyl-7--3-carbonyl)-amino]-acetic acid
Be similar to example D-55e), make from example D-45a) butyl ester and the mixture reaction of 0.142g glycine in the 2.5ml0.5M methanol solution of sodium methylate obtain 0.042g.MS-(-)-ion, M-1=373.0amu.
Example D-46
[(the bromo-4-hydroxyl of 1--7-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-hydroxyl-7-methyl isophthalic acid-oxygen-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43a)-D-43c) reaction sequence after, 5.0g4-methyl-phthalic acid produces 0.213g4-hydroxyl-7-methyl isophthalic acid-oxygen-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(-)-ion, M-1=274.1amu.
B) the bromo-4-hydroxyl of 1--7-methyl-isoquinoline-3-carboxylic acid butyl ester
Will be from example D-46a) the 0.210g ester products be added in the 3.5ml acetonitrile.Add 1.52g bromine phosphorus oxide and by this mixture backflow 6h, cooling and be dissolved in ethyl acetate.Use saturated NaHCO 3aqueous cleaning ethyl acetate solution, drying (MgSO 4), filter and concentrate to produce the 0.266g crude product.Crude product is used to silica gel chromatography (elutriant: methylene dichloride) to produce 0.094g white solid: proton N MR (200MHz, chloroform-d): δ 11.85 (s, 1H), 8.30-8.20 (d, 1H), 8.00 (br s, 1H), 7.70-7.60 (m, 1H), 4.47 (t, J=7Hz, 2H), (2.62 s, 3H), 1.95-1.75 (m, 2H), 1.60-1.35 (m, 2H), (1.00 t, J=7Hz, 3H).
C) [(the bromo-4-hydroxyl of 1--7-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-55e), make 0.094g from example D-46b) butyl ester and the mixture reaction of 0.312g glycine in the 5.5ml0.5M methanol solution of sodium methylate produce 0.083g creamy white solid: MS-(-)-ion, M-1=339.0amu.
Example D-47
[(the bromo-7-butoxy of 1--4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-7-butoxy of 1--4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-46b), make 0.150g7-butoxy-4-hydroxyl-1-oxygen-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester reacts to produce 0.105g creamy white solid with the bromine phosphorus oxide: proton N MR (200MHz, chloroform-d): δ 11.82 (s, 1H), 8.68 (s, 1H), 8.26 (d, 1H), (7.35 dd, 1H), 7.19 (d, 1H), 4.49 (t, J=7Hz, 2H), (4.12 t, J=7Hz, 2H), 1.95-1.75 (m, 4H), 1.70-1.40 (m, 4H), (1.05-0.95 m, 6H).
B) [(the bromo-7-butoxy of 1--4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-11e), make 0.100g from example D-47a) butyl ester and the mixture reaction of glycine in methanol solution of sodium methylate to produce the 0.094g white solid: MS-(-)-ion, M-1=397.0amu.
Example D-48
[(the bromo-6-butoxy of 1--4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-6-butoxy of 1--4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-46b), make 0.175g6-butoxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and bromine phosphorus oxide react to produce 0.073g white solid: proton N MR (200MHz, chloroform-d): δ 11.84 (s, 1H), 8.13 (d, 1H), 7.60 (m, 1H), 7.42-7.35 (m, 1H), 4.48 (t, J=7Hz, 2H), 4.15 (t, J=7Hz, 2H), 1.95-1.75 (m, 4H), 1.65-1.40 (m, 4H), 1.05-0.95 (m, 6H).
B) [(the bromo-6-butoxy of 1--4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-43e), make 0.068g from example D-48a) butyl ester and the mixture reaction of glycine in methanol solution of sodium methylate to produce 0.063g creamy white solid: MS-(-)-ion, M-1=397.0amu.
Example D-49
[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid
By 0.33g6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid, 0.5ml triethylamine, 0.400g HATU and 0.165g N-methyl-amino-ethyl acetate hydrochloride in the 15ml methylene dichloride mixed and at room temperature stirred reaction mixture 18h to produce 0.232g creamy white solid, MS-(+)-ion: 429.0amu after silica gel chromatography.Be dissolved in 10ml NaOH methanol solution (1.5M) by this intermediate product of 0.208g and at room temperature stir this mixture 3h.Remove solvent with rotary evaporator, resistates is dissolved in the water and uses 50ml ethyl acetate aqueous layer extracted.With the HCl aqueous solution, by the water layer acidifying, be that pH=1 is to produce solid sediment.Collect solid by suction filtration, water cleans and is dry to produce the 0.180g white solid in vacuum drying oven (80 ℃): MS-(+)-ion: 401.0amu.
Example D-50
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid
Be similar to example D-49, prepared by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid: MS-(+)-ion: 294.9amu.
Example D-51
[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid
Be similar to example D-49, prepared by 1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid: MS-(+)-ion: 353.0amu.
Example D-52
[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid
Be similar to example D-49, prepared by 1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid: MS-(+)-ion: 353.0amu.
Example D-53
[carboxymethyl-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-49, prepared by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and (oxyethyl group carbonyl methyl-amino)-ethyl acetate: MS-(+)-ion: 339.0amu.
Example D-54
[carboxymethyl-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-49, prepared by 1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid and (oxyethyl group carbonyl methyl-amino)-ethyl acetate: MS-(+)-ion: 397.0amu.
Example D-55
{ [4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and naphthalene-2-alcohol; MS-(+)-ion: M+1=388.1.
B) { [4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=389.1.
Example D-56
{ [4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and pyridine-3-alcohol; MS-(+)-ion: M+1=339.1.
B) { [4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=340.1.
Example D-57
{ [4-hydroxyl-1-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-hydroxyl-1-(4-methoxyl group-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-20d), by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 4-methoxyl group-phenol synthesis; MS-(+)-ion: M+1=368.1.
B) { [4-hydroxyl-1-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-(4-methoxyl group-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=369.1.
Example D-58
{ [4-hydroxyl-1-(3-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-hydroxyl-1-(3-methoxyl group-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 3-methoxyphenol; MS-(+)-ion: M+1=368.1.
B) { [4-hydroxyl-1-(3-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-(3-methoxyl group-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=367.0.
Example D-59
{ [1-(the fluoro-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 1-(the fluoro-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 3-fluorophenol; MS-(+)-ion: M+1=356.1.
B) { [1-(the fluoro-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 1-(the fluoro-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=357.09.
Example D-60
{ [1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 4-fluorophenol; MS-(+)-ion: M+1=356.1.
B) { [1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=357.0.
Example D-61
{ [1-(the fluoro-phenoxy group of 2-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 1-(the fluoro-phenoxy group of 2-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 2-fluorophenol; MS-(+)-ion: M+1=356.1.
B) { [1-(the fluoro-phenoxy group of 2-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 1-(the fluoro-phenoxy group of 2-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=357.11.
Example D-62
{ [4-hydroxyl-1-(2-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-hydroxyl-1-(2-methoxyl group-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 2-methoxyphenol; MS-(+)-ion: M+1=368.13.
B) { [4-hydroxyl-1-(2-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-(2-methoxyl group-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=369.09.
Example D-63
{ [1-(4-acetylaminohydroxyphenylarsonic acid phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-acetoxyl group-1-(4-acetylaminohydroxyphenylarsonic acid phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
At ambient temperature by 4-hydroxyl-1-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (261mg, 0.77mmol; See example D-20d) be dissolved in dense H 2sO 4(4ml) in.Solution is cooled to 0 ℃ and also under agitation slowly adds KNO 3(79mg, 0.77mmol).Mixture is stirred to 2h under 0 ℃, then under agitation be injected in frozen water (100ml).Extract this mixture with EtOAc (3 * 30ml).Use NaHCO 3the aqueous solution and salt solution clean and merge organic phase, dry and concentrated in a vacuum.Resistates is dissolved in the mixture of EtOAc (20ml) and MeOH (10ml).Add sodium acetate (70mg, 0.85mmol) and Pd/C (75mg, 10 % by weight Pd) and at H 2stir this mixture 24h in envrionment temperature under-atmosphere (1atm).Then by Celite pad, filter this mixture.Clean diatomite and filter cake and concentrate in a vacuum with hot MeOH (3 * 4ml) and merge organic phase.150mg gained resistates (is amounted to: 380mg) be dissolved in EtOAc (8ml).Add triethylamine (325 μ l, 2.3mmol) and solution is cooled to 0 ℃.Then under vigorous stirring, slowly add diacetyl oxide (110 μ l, 1.15mmol).Make this mixture temperature to envrionment temperature also then stir again at ambient temperature whole night 20h.Add subsequently EtOAc (50ml).Use NaHCO 3the aqueous solution and salt solution washed mixture, dry and concentrated in a vacuum.Use CH on silica gel by flash chromatography 2cl 2: MeOH=100:1 to 100:3 comes the purifying resistates to produce 150mg4-acetoxyl group-1-(4-acetylaminohydroxyphenylarsonic acid phenoxy group)-isoquinoline-3-carboxylic acid butyl ester as elutriant; MS-(+)-ion: M+1=437.11.
B) { [1-(4-acetylaminohydroxyphenylarsonic acid phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Under agitation by 4-acetoxyl group-1-(4-acetylaminohydroxyphenylarsonic acid phenoxy group)-isoquinoline-3-carboxylic acid butyl ester (150mg, 0.34mmol), the mixture backflow complete cycle of methyl alcohol (3.9mmol) solution of glycine (290mg, 3.4mmol) and 7.8ml0.5N sodium methylate.Then evaporating solvent resistates is dissolved in 25ml water in a vacuum.Subsequently the pH value of this solution is adjusted into approximately and 2 also by ethyl acetate (3 * 30ml), extracts the slurries of gained.Via MgSO 4dry combining extraction liquid evaporation in a vacuum.Make resistates from methyl alcohol/CH 2cl 2middle recrystallize produces the 86mg title compound; MS-(+)-ion: M+1=396.15.
Example D-64
{ [4-hydroxyl-1-(4-methanesulfonamido-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
At ambient temperature by 4-hydroxyl-1-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (261mg, 0.77mmol; See example D-20d) be dissolved in dense H 2sO 4(4ml) in.Solution is cooled to 0 ℃ and also under agitation slowly adds KNO 3(79mg, 0.77mmol).Mixture is stirred to 2h under 0 ℃, then under agitation be injected in frozen water (100ml).Extract this mixture with EtOAc (3 * 30ml).Use NaHCO 3the aqueous solution and salt solution clean and merge organic phase, dry and concentrated in a vacuum.Resistates is dissolved in the mixture of EtOAc (20ml) and MeOH (10ml).Add sodium acetate (70mg, 0.85mmol) and Pd/C (75mg, 10 % by weight Pd) and at H 2stir this mixture 24h in envrionment temperature under-atmosphere (1atm).Then by Celite pad, filter this mixture.Clean diatomite and filter cake and concentrate in a vacuum with hot MeOH (3 * 4ml) and merge organic phase.150mg gained resistates (is amounted to: 380mg) be dissolved in CH 2cl 2(8ml) in.Add triethylamine (165 μ l) and solution be cooled to-20 ℃.Then under vigorous stirring, slowly add MeSO 2cl (36 μ l).Make this mixture temperature to envrionment temperature also then stir again at ambient temperature whole night 20h.Add subsequently EtOAc (50ml).Use NaHCO 3the aqueous solution and salt solution washed mixture, dry and concentrated in a vacuum.Use CH on silica gel by flash column chromatography 2cl 2: MeOH=100:0-100:3 carrys out the purifying resistates as elutriant.Methyl alcohol (3.9mmol) solution of glycine (290mg, 3.4mmol) and 7.8ml0.5N sodium methylate is added in purified product (168mg) and by this mixture and under agitation refluxes a weekend.Then evaporating solvent resistates is dissolved in 30ml water in a vacuum.Subsequently the pH value of this solution is adjusted into approximately and 2 also by ethyl acetate (3 * 30ml), extracts the mixture of gained.Via MgSO 4dry combining extraction liquid evaporation in a vacuum.Make resistates from methyl alcohol/CH 2cl 2middle recrystallize produces the 89mg title compound; MS-(+)-ion: M+1=432.12.
Example D-65
[(4-hydroxyl-1-phenyl amino-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-hydroxyl-1-phenyl amino-isoquinoline-3-carboxylic acid butyl ester
150 ℃ of mixture 20min that stir the bromo-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester (810mg, 2.5mmol, example D-28a) and aniline (3ml) in penstock in microwave oven.Merge two kinds of reaction mixtures, add EtOAc (100ml) and use H 2o (5 * 30ml, pH=1-2) cleans this mixture.Dry organic phase is also concentrated in a vacuum.By flash chromatography, on silica gel, make hexane/EtOAc come the purifying resistates to produce 770mg4-hydroxyl-1-phenyl amino-isoquinoline-3-carboxylic acid butyl ester as elutriant; MS-(+)-ion: M+1=337.21.
B) [(4-hydroxyl-1-phenyl amino-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by hydroxyl-1-phenyl amino-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=338.14.
Example D-66
{ [4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(pyridin-3-yl oxygen base)-phthalonitrile
Stir at ambient temperature 4-nitro-phthalonitrile (3.46g, 20mmol), pyridine-3-alcohol (1.90g, 20mmol), K 2cO 3the mixture of (8.29g, 60mmol) and DMF (50ml) whole night.Then by reaction mixture and another batch of merging carrying out same reaction on identical scale.Remove solid constituent concentrating filtrate in a vacuum by filtration subsequently.Water (15ml) is added in resistates and with EtOAc and extracts this mixture.Then with salt solution, clean organic phase, dry and evaporation in a vacuum.Make resistates from EtOAc/MeOH recrystallize to produce the 8.3g title compound; 1h NMR (CDCl 3): δ=8.56-8.59 (m, 1H), 8.45-8.47 (m, 1H), 7.76 (d, 1H), 7.42-7.44 (m, 2H), 7.22-7.32 (m, 2H).
B) 4-(pyridin-3-yl oxygen base)-phthalic acid
Be similar to example D-1a) synthetic by 4-(pyridin-3-yl oxygen base)-phthalonitrile; MS-(+)-ion: M+1=260.2.
C) [1,3-dioxy-5-(pyridin-3-yl oxygen base)-1,3-dihydro-isoindole-2-yl]-acetic acid
Be similar to example D-1b) synthetic by 4-(pyridin-3-yl oxygen base)-phthalic acid; MS-(+)-ion: M+1=299.25.
D) [1,3-dioxy-5-(pyridin-3-yl oxygen base)-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to example D-1c) synthetic by [1,3-dioxy-5-(pyridin-3-yl oxygen base)-1,3-dihydro-isoindole-2-yl]-acetic acid; MS-(+)-ion: M+1=313.21.
E) Isosorbide-5-Nitrae-dihydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and Isosorbide-5-Nitrae-dihydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) synthetic by [1,3-dioxy-5-(pyridin-3-yl oxygen base)-1,3-dihydro-isoindole-2-yl]-methyl acetate.But, after adding 2N HCl (the pH value is adjusted into to 8-9), with EtOAc, extract this mixture 3 times.The dry organic phase concentrated in a vacuum that merges.Process resistates and store whole night in refrigerator with MeOH.Filter formed throw out, clean and dry with the be white in color regional isomerism mixture of title compound of solid of generation in a vacuum with a small amount of cold MeOH.Isosorbide-5-Nitrae-dihydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester does not separate with Isosorbide-5-Nitrae-dihydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=355.09.
F) 1-chloro-4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and 1-chloro-4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d), by [the regional isomerism mixture of Isosorbide-5-Nitrae-dihydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and Isosorbide-5-Nitrae-dihydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester synthesizes.This regional isomer does not separate; MS-(+)-ion: M+1=373.01.
G) 4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (A) and 4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to example D-7f), by the regional isomerism mixture of 1-chloro-4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and 1-chloro-4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester, synthesized.Use CH on silica gel by flash column chromatography 2c1 2: EtOAc (90:10 to 80:20) wash-out carrys out the separated region isomer.Evaporate the first elution fraction and obtain B; MS-(+)-ion: M+1=339.09.Evaporate the second elution fraction and obtain A; MS-(+)-ion: M+1=339.10.
H) { [4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=340.06.
Example D-67
{ [4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=340.06.
Example D-68
[(1-chloro-4-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) [(1-chloro-4-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (56mg, 0.2mmol under agitation refluxes; Can be according to the people's such as Weidmann United States Patent (USP) 6,093,730,10/1998 obtains), Me 2sO 4(57 μ l, 0.6mmol), KHCO 3the mixture 48h of (306mg, 3mmol) and acetone (4ml).After this evaporating solvent water (4ml) is added in resistates.Extract this mixture with EtOAc (3 * 20ml).Via MgSO 4the dry organic phase that merges also evaporates to produce brown oil in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=7:3 carrys out purifying as elutriant, produces the title compound (21mg) that is light yellow oil; MS-(+)-ion: M+1=308.9.
B) [(1-chloro-4-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Stir at ambient temperature the mixture 3h of [(1-chloro-4-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate (21mg, 0.07mmol), KOH (23mg, 0.35mmol) and EtOH (1ml).Follow evaporating solvent in a vacuum.Resistates is dissolved in water (2ml) and by adding the 1N HCl aqueous solution pH of this solution is adjusted into to 2-3.Extract this mixture with EtOAc (4 * 10ml).Via MgSO 4the dry organic phase that merges also evaporates to produce the title compound (18mg) that is slight yellow solid in a vacuum; MS-(+)-ion: M+1=295.0.
Example D-69
[(the chloro-4-oxyethyl group-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
A) [(the chloro-4-oxyethyl group-isoquinoline 99.9 of 1--3-carbonyl)-amino]-ethyl acetate
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (56mg, 0.2mmol under agitation refluxes; Can be according to the people's such as Weidmann United States Patent (USP) 6,093,730,10/1998 obtains), Et 2sO 4(59 μ l, 0.44mmol), KHCO 3(306mg, 3mmol) and Et 2the mixture 18h of CO (3ml).Follow evaporating solvent and water (4ml) is added in resistates.This mixture of vigorous stirring 5min.Then filter.By filter cake, be dissolved in EtOAc and via MgSO 4dry this solution.Concentrate in a vacuum this solution.Be dissolved in EtOAc (0.5ml) by the gained brown solid and add hexane.Store at ambient temperature this mixture 14h, then solvent is poured out from formed throw out.Dry sediment is with the be white in color title compound (8mg) of crystal of generation in a vacuum; MS-(+)-ion: M+1=337.0.
B) [(the chloro-4-oxyethyl group-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
Be similar to example D-68b), synthetic by [(the chloro-4-oxyethyl group-isoquinoline 99.9 of 1--3-carbonyl)-amino] ethyl acetate; MS-(+)-ion: M+1=309.0.
Example D-70
{ [4-hydroxyl-1-methoxy-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
At ambient temperature by Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (26.13g, 100mmol; Example D-20b), PhCH 2the mixture of Br (18.2ml, 150mmol), MeONa (0.5M in MeOH, 200ml, 100mmol) stirs 48h.Follow evaporating solvent and EtOAc (100ml) is added in resistates.This mixture of vigorous stirring 10min.Then filter.Clean filtrate with the 2.5N NaOH aqueous solution (2 * 100ml) and the 2N HCl aqueous solution (1 * 100ml).Via MgSO 4dry organic phase evaporation in a vacuum.Make resistates recrystallize from MeOH (500ml)/water (300ml).Use hexane: EtOAc:NEt on silica gel by flash column chromatography 3=65:30:5 is further purified the gained yellow solid to produce the 10.8g yellow solid as elutriant.Use hexane: EtOAc:NEt on silica gel by flash column chromatography 3=75:20:5 is further purified this material of 2g as elutriant and is the title compound of slight yellow solid to produce 1.57g; 1h NMR (CDC1 3): δ=8.88 (bs, 1H), 8.46 (d, 1H), 8.42 (d, 1H), 7.26-7.96 (m, 7H), 5.06 (s, 2H), 4.38 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.91 (t, 3H).
B) 4-benzyloxy-1-methoxyl group-isoquinoline-3-carboxylic acid butyl ester
At ambient temperature by 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (1 equivalent), Me 3oBF 4(6 equivalent), KHCO 3(14 equivalent) and CH 2c1 2the mixture of (10ml/mmol4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester) stirs 24h.Then add water (10ml/mmol) and use CH 2cl 2(40ml/mmol) extract this mixture.Separate organic phase, via MgSO 4drying also evaporates to produce micro-yellow solid in a vacuum.By flash column chromatography, on silica gel, use hexane: EtOAc=85:15 to carry out the purification of crude product as elutriant.Evaporate the first elution fraction and be the title compound of colorless oil with generation, productive rate is 20%; 1h NMR (CDCl 3): δ=8.21-8.25 (m, 1H), 8.05-8.09 (m, 1H), 7.33-7.73 (m, 7H), (5.13 s, 2H), 4.38 (t, 2H), 4.16 (s, 3H), (1.69 m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
C) 4-hydroxyl-1-methoxy-isoquinoline-3-carboxylic acid butyl ester
At H 2stir the mixture 16h of 4-benzyloxy-1-methoxyl group-isoquinoline-3-carboxylic acid butyl ester (164mg, 0.45mmol), Pd/C (50mg, 10 % by weight Pd) and EtOAc (15ml) under-atmosphere at environmental stress and temperature.Then by Celite pad, filter this mixture.With EtOAc thoroughly clean diatomite and filter cake and in a vacuum the concentrated organic phase that merges with the be white in color title compound (115mg) of solid of generation; 1hNMR (CDCl 3): δ=11.48 (s, 1H), 8.27-8.32 (m, 1H), 8.17-8.21 (m, 1H), (7.65-7.78 m, 2H), 4.43 (t, 2H), 4.10 (s, 3H), (1.87 m, 2H), 1.54 (m, 2H), 1.02 (t, 3H).
D) [(4-hydroxyl-1-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-methoxy-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=275.0.
Example D-71
[(1-oxyethyl group-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 1-oxyethyl group-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Stir at ambient temperature 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (422mg, 1.2mmol, example D-70a), KHCO 3(2.22g, 22mmol) and 1M are at CH 2cl 2et in (10ml, 10mmol) 3oBF 4mixture 16h and then under agitation reflux 3 days.According to TLC, 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester does not react under these conditions.Therefore, add other KHCO 3(2.22g, 22mmol) and 1M are at CH 2cl 2et in (10ml, 10mmol) 3oBF 4, and this mixture is concentrated in a vacuum.Subsequently, add 1,2-ethylene dichloride (10ml) this mixture 16h that under agitation refluxes.Follow evaporating solvent in a vacuum.Water (25ml) is added in resistates and extracts this mixture with EtOAc (2 * 50ml).Via MgSO 4the dry organic phase that merges also evaporates to produce micro-yellow solid (374mg) in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=85:15 carrys out purifying as elutriant, obtains micro-yellow oil (104mg).Reuse hexane: EtOAc=99:2 and subsequently 99:1 as the chromatography purification of elutriant, obtain being the title compound (60mg) of water white oil; 1h NMR (CDC1 3): δ=11.45 (s, 1H), 8.20-8.32 (m, 2H), 7.64-7.78 (m, 2H), 4.38-4.59 (m, 4H), 1.84 (m, 2H), 1.54 (m, 5H), 1.01 (t, 3H).
B) [(1-oxyethyl group-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 1-oxyethyl group-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=291.0.
Example D-72
[(4-oxyethyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) [(1-oxygen-3-phenyl-1H-indenes-2-carbonyl)-amino]-methyl acetate
1-oxygen-3-phenyl-lH-indenes-2-formic acid (2.13g, 8.5mmol under agitation refluxes; Can according to the people such as M.R.Barvian the 7th phase in 1997 " bioorganic chemistry and pharmaceutical chemistry communication " (Bioorg.Med.Chem.Lett.) description of 2903-2908 page obtain) and SOC1 2(17ml) mixture 15min.Then evaporate in a vacuum excessive SOC1 2.Resistates is dissolved in to anhydrous CH 2cl 2(20ml) also again concentrate in a vacuum subsequently this solution in to remove last micro-SOCl 2.Resistates is dissolved in to anhydrous CH 2cl 2(20ml) in.With cooling this solution of ice bath, then under agitation add glycine methyl ester hydrochloride (1.27g, 10mmol) and add subsequently NEt 3(3.52ml, 25mmol dropwise add).Then remove ice bath and continue to stir at ambient temperature 45min, then enriched mixture in a vacuum.Water (10ml) and the 2N HCl aqueous solution (15ml) are added in resistates and extract this mixture by ethyl acetate (1 * 70ml).Via MgSO 4dry organic phase also evaporates to produce safran solid (2.77g) in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=2:1 carrys out purifying as elutriant, produces the title compound (2.11g) that is the safran solid; MS-(+)-ion: M+1=322.0.
B) [(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate
With 50 to 60 ℃ [(1-oxygen-3-phenyl-lH-indenes-2-carbonyl)-amino]-methyl acetate (1.864g, 5.8mmol) is dissolved in to dense H 2sO 4(16ml) and in the mixture of Glacial acetic acid (16ml).Then NaN is added under agitation gradation 3(985mg, 15mmol) makes temperature be no more than 60 ℃.Then at 50 to 60 ℃, continue again to stir 30min, then this mixture is annotated on ice (200g).By adding dense NH 3the aqueous solution (55ml, D=0.89g/ml) alkalizes the mixture of gained use CH 2cl 2(2 * 100ml) extraction.Via MgSO 4the dry organic phase that merges is also then filtered by silica gel.Filtrate is abandoned.Clean silica gel with EtOAc (about 400ml).Concentrated gained solution is to produce black oil (250mg) in a vacuum.Use EtOAc by flash column chromatography and then use EtOAc: hexane=7:3 to be further purified to produce the title compound (19mg) that is the brown color solid as elutriant on silica gel; 1h NMR (CDCl 3): δ=7.11-7.98 (m), 3.75 (d, 2H), 3.68 (s, 1H), 2.19 (s, 3H).
C) [(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
At ambient temperature the mixture of [(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate (3.8mg, 0.01mmol) and the 6N HCl aqueous solution (1ml) is stirred to 16h, then by adding dense NaHCO 3the aqueous solution is adjusted into approximately 8 by the pH value of this solution.Clean this solution with EtOAc (2 * 10ml), then by adding the 2N HCl aqueous solution by its acidifying.Use subsequently EtOAc (2 * 10ml) to extract this mixture.Via MgSO 4the dry organic phase that merges also evaporates to produce the title compound (1.9mg) that is yellow oily in a vacuum; MS-(+)-ion: M+1=364.9.
Example D-73
[(4-hydroxyl-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-hydroxyl-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester
Under agitation by 4-acetoxyl group-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester (671mg, 2mmol; Can according to people such as D.A.Walsh, the description in the 21st phase in 1978 " pharmaceutical chemistry magazine " 582-585 page obtains), n-BuOH (60ml) and dense H 2sO 4(1.7ml) mixture backflow 4h, then under agitation be added into reaction mixture dense NaHCO 3in the aqueous solution (60ml).Then add EtOAc (120ml) this mixture of vigorous stirring 15min.Separate subsequently organic phase, via MgSO 4dry and concentrated in a vacuum.By flash column chromatography, on silica gel, use hexane: EtOAc=95:5 to carry out the purifying resistates as elutriant, produce solid title compound (126mg); 1h NMR (CDCl 3): δ=11.96 (s, 1H), 8.44-8.49 (m, 1H), 8.01-8.05 (m, 1H), 7.43-7.80 (m, 7H), 4.56 (q, 2H), 1.49 (t, 3H).
B) [(4-hydroxyl-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester; MS-(+)-ion: M+1=323.1.
Example D-74
[(1-oxyethyl group-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the chloro-4-phenyl of 1--isoquinoline-3-carboxylic acid ethyl ester
Under agitation by 1-hydroxy-4-phenyl-isoquinoline-3-carboxylic acid ethyl ester (1.17g, 4mmol; Can in the description of the 52nd phase Ann.Chim. (Rome) 112-120 page in 1962, obtain according to people such as A.Marsili) and dense POCl 3(10ml) mixture backflow 1h.Then concentrate in a vacuum this mixture.Resistates is dissolved in EtOAc (50ml), adds dense NaHCO 3the aqueous solution (40ml) this mixture of vigorous stirring 1h.Separate subsequently organic phase.Via MgSO 4the dry title compound (1.20g) that is micro-yellow solid with generation that also concentrates in a vacuum; MS-(+)-ion: M+1=312.0.
B) [(the chloro-4-phenyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-methyl acetate
Under agitation by the mixture backflow 2.5h of the chloro-4-phenyl of 1--isoquinoline-3-carboxylic acid ethyl ester (1.184g, 3.8mmol), the 2N NaOH aqueous solution (15ml, 30mmol) and EtOH (15ml).Then this mixture is concentrated into to 1/2 of its volume.Subsequently, by adding dense this solution of HCl acidifying and extracting gained suspension with EtOAc (2x50ml).Via MgSO 4the dry organic phase that merges also evaporates to produce micro-yellow solid (1.018g) in a vacuum.By SOCl 2(7ml) be added in this micro-yellow solid of 996mg also under agitation by this mixture backflow 1h.Then by excessive SOCl 2evaporation in a vacuum.Resistates is dissolved in to anhydrous CH 2cl 2(10ml) also again concentrate in a vacuum subsequently this solution in to remove last micro-SOCl 2.Resistates is dissolved in to anhydrous CH 2cl 2(8ml) in.With cooling this solution of ice bath, then under agitation add glycine methyl ester hydrochloride (507mg, 4mmol) and add subsequently NEt 3(1.55ml, 11mmol dropwise add).Then remove ice bath and continue at ambient temperature to stir 1h, then concentrate in a vacuum this mixture.Water (15ml) is added in resistates and extracts this mixture with EtOAc (1 * 50ml).Via MgSO 4dry organic phase also evaporates to produce brown color solid (1.07g) in a vacuum.From MeOH (30ml)/water (10ml), recrystallize produces the title compound (430mg) that is slight yellow solid; MS-(+)-ion: M+1=355.0.
C) [(1-oxyethyl group-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Stir at ambient temperature [(the chloro-4-phenyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-methyl acetate (177mg, 0.5mmol), KOH (325mg, 5mmol) and the mixture 90min of EtOH (10ml), evaporating solvent in a vacuum then.Resistates is dissolved in water (10ml).Carry out this solution of acidifying and extract with EtOAc (2 * 15ml) by adding the dense HCl aqueous solution.Via MgSO 4the dry organic phase that merges also concentrates the title compound (169mg) that is slight yellow solid with generation in a vacuum; MS-(+)-ion: M+1=351.0.
Example D-75
[(the chloro-4-phenyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid
At ambient temperature the mixture of [(the chloro-4-phenyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-methyl acetate (50mg, 0.14mmol, example D-74b) and the 6N HCl aqueous solution is stirred 11 days, then by adding dense NaHCO 3the aqueous solution neutralizes this solution.Extract this mixture with EtOAc (50ml).Via MgSO 4dry organic phase is also concentrated with the be white in color title compound (35mg) of solid of generation in a vacuum; MS-(+)-ion: M+1=341.0.
Example D-76
[(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) [(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate
At H 2stir [(the chloro-4-phenyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-methyl acetate (177mg under-atmosphere at environmental stress and temperature, 0.5mmol, example D-74b), Pd/C (50mg, 10 % by weight Pd), the mixture 2h of sodium acetate (49mg, 0.6mmol), MeOH (10ml) and EtOAc (5ml).Then by Celite pad, filter this mixture.Thoroughly clean diatomite and filter cake and concentrate in a vacuum with EtOAc and merge organic phase.By dense NaHCO 3the aqueous solution (10ml) is added in resistates and extracts this mixture with EtOAc (2 * 15ml).Via MgSO 4the dry organic phase that merges also concentrates and is the title compound (154mg) without coloring agent with generation in a vacuum; MS-(+)-ion: M+1=321.0.
B) [(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Stir at ambient temperature the mixture 18h of [(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate (144mg, 0.45mmol), KOH (325mg, 5mmol) and EtOH (10ml), then evaporating solvent in a vacuum.Resistates is dissolved in the water.By adding the dense HCl aqueous solution, the pH value of this solution is adjusted into to 3-4.Then with EtOAc (2 * 25ml), extract this solution.Via MgSO 4the dry organic phase that merges also concentrates the title compound (127mg) that is micro-yellow solid with generation in a vacuum; MS-(+)-ion: M+1=307.1.
Example D-77
[(4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl-isoquinoline-3-carboxylic acid of 1-
Under agitation by the bromo-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester (8.18g, 25mmol; Example D-28a), the mixture backflow 2h of the 2N NaOH aqueous solution (80ml, 160mmol) and EtOH (80ml).Then concentrated this solution is to the l/2 of its volume in a vacuum, and water (200ml) dilute and passes through the dense HCl acidified aqueous solution of interpolation.Make the vacuum filtration of gained suspension after stirring at ambient temperature 1h.Water thoroughly clean filter cake in a vacuum in 75 ℃ of dryings with the be white in color title compound (6.10g) of solid of generation; 1hNMR (DMSO-d 6): δ=8.30-8.37 (m, 1H), 8.16-8.22 (m, 1H), 7.93-8.03 (m, 2H).
B) 4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid methyl esters
Under agitation in-78 ℃ of hexanes by 2.5M n-BuLi (4ml, 10mmol) solution, slowly be added in anhydrous THF (100ml) solution of the bromo-4-hydroxyl-isoquinoline-3-carboxylic acid of l-(670mg, 2.5mmol).Add MeI (316 μ l, 5mmol) after stirring 5min again.10min is stirred again in continuation under-78 ℃, then adds water (50ml) and the 2N HCl aqueous solution (6ml).Under agitation make this mixture temperature to envrionment temperature and then be concentrated in a vacuum approximately 1/2 of its volume.By the throw out sucking-off of gained, water cleans, in a vacuum in 80 ℃ of dryings and from EtOH recrystallize produce light brown yellow solid (141mg).The above-mentioned light brown yellow solid of the 102mg that under agitation refluxes, Me 2sO 4(48ml, 0.5mmol), KHCO 3the mixture 15h of (1.0g, 10mmol) and acetone (10ml).Then concentrate in a vacuum this mixture.Water (20ml) is added in resistates and extracts this mixture with EtOAc (3 * 20ml).Via MgSO 4the dry organic phase that merges also concentrates the title compound that is the brown color solid with generation in a vacuum; 1h NMR (CDCl 3): δ=11.66 (s, 1H), 8.39-8.44 (m, 1H), 8.02-8.09 (m, 1H), 7.74-7.81 (m, 2H), 4.08 (s, 3H), 2.90 (s, 3H).
C) [(4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid methyl esters; MS-(-)-ion: M-1=259.0.
Example D-78
[(4-hydroxyl-1-methoxy methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid benzyl ester
Under agitation in-78 ℃ of hexanes by 2.5M n-BuLi (4ml, 10mmol) solution, slowly be added into l-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid (670mg, 2.5mmol; Example D-77a) in anhydrous THF (100ml) solution.Add MeOCH after stirring 5min again 2i (446 μ l, 5mmol).5min is stirred again in continuation under-78 ℃, then adds water (50ml) and the 6N HCl aqueous solution (2ml).Under agitation make this mixture temperature to envrionment temperature and then be concentrated in a vacuum approximately 1/3 also extracting with EtOAc (50ml) of its volume.Clean organic phase with water (10ml) solution of Sodium Pyrosulfite (0.5g), then via MgSO 4dry and concentrated to produce micro-yellow solid (432mg) in a vacuum.
The above-mentioned micro-yellow solid of the 429mg that under agitation refluxes, bromotoluene (0.6ml, 5mmol), K 2cO 3the mixture of (2.07g, 15mmol) and acetone (40ml) 2.5 days.Then concentrate in a vacuum this mixture.Water (40ml) is added in resistates and extracts this mixture with EtOAc (50ml).Via MgSO 4dry organic phase is also concentrated to produce brown oil in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=6:4 carrys out purifying as elutriant, produces the title compound (201mg) that is yellow oil; MS-(+)-ion: M+1=414.1.
B) 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid
Stir at ambient temperature the mixture 18h of 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid benzyl ester (198mg, 0.48mmol), KOH (325mg, 5mmol) and EtOH (10ml), then evaporating solvent in a vacuum.Water (25ml) is added in resistates and uses Et 2o (2 * 25ml) cleans this mixture.Then by adding the 6N HCl aqueous solution, carry out this solution of acidifying and extract with EtOAc (25ml).Via MgSO 4dry organic phase also concentrates the title compound (140mg) that is yellow oil with generation in a vacuum; MS-(+)-ion: M+1=324.1.
C) [(4-benzyloxy-1-methoxymethyl-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Under agitation by ClCO 2iBu (52 μ l, 0.39mmol) is added into the 4-benzyloxy cooling with ice bath-1-methoxymethyl-isoquinoline-3-carboxylic acid (120mg, 0.37mmol), NEt 3(109 μ l, 0.78mmol) and CH 2cl 2(7ml) in mixture.After stirring 15min, add glycine benzyl hydrochloride (79mg, 0.39mmol) and separately stir again this mixture 15min, then remove ice bath.Then continue to stir again at ambient temperature 1.5h.Concentrate in a vacuum subsequently this mixture.Water (10ml) and several 6N HCl aqueous solution are added in resistates.Extract this mixture with EtOAc (15ml).Via MgSO 4dry organic phase is also concentrated to produce micro-yellow glue in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=7:3 carrys out purifying as elutriant, produces the title compound (141mg) that is yellow oil; MS-(+)-ion: M+1=471.1.
D) [(4-hydroxyl-1-methoxy methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
At H 2stir [(4-benzyloxy-1-methoxymethyl-isoquinoline 99.9-3-carbonyl)-amino]-jasmal (134mg under-atmosphere at environmental stress and temperature, 0.285mmol), the mixture 18h of Pd/C (100mg, 10 % by weight Pd) and EtOAc (10ml).Then by Celite pad, filter this mixture.Thoroughly clean diatomite and filter cake and concentrate in a vacuum the merging organic phase with EtOAc and be the title compound (74mg) of brown color solid with generation; MS-(-)-ion: M-1=289.2.
Example D-79
[(1-dimethylamino formyl radical-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-benzyloxy-1-dimethylamino formyl radical-isoquinoline-3-carboxylic acid benzyl ester
Under agitation in-78 ℃ of hexanes by 2.5M n-BuLi (4ml, 10mmol) solution, slowly be added into l-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid (670mg, 2.5mmol; Example D-77a) in anhydrous THF (100ml) solution.Add ClCONMe after stirring 5min again 2(468 μ l, 5mmol).5min is stirred again in continuation under-78 ℃, then adds water (50ml) and the 6N HCl aqueous solution (2ml).Under agitation make this mixture temperature to envrionment temperature and then be concentrated in a vacuum approximately 1/3 also extracting with EtOAc (2 * 50ml) of its volume.Via MgSO 4the dry organic phase concentrated to produce yellow solid (501mg) in a vacuum that merges.The above-mentioned yellow solid of 492mg, bromotoluene (0.6ml, 5mmol), K under agitation reflux 2cO 3the mixture of (2.07g, 15mmol) and acetone (40ml) 2.5 days.Concentrate in a vacuum subsequently this mixture.Water (20ml) is added in resistates and extracts this mixture with EtOAc (50ml).Via MgSO 4dry organic phase is also concentrated to produce brown oil in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=6:4 carrys out purifying as elutriant, produces the title compound (311mg) that is yellow oil; MS-(+)-ion: M+1=441.1.
B) 4-benzyloxy-1-dimethylamino formyl radical-isoquinoline-3-carboxylic acid
Stir at ambient temperature the mixture 18h of 4-benzyloxy-1-dimethylamino formyl radical-isoquinoline-3-carboxylic acid benzyl ester (308mg, 0.7mmol), KOH (325mg, 5mmol) and EtOH (10ml), then evaporating solvent in a vacuum.Water (25ml) is added in resistates and uses Et 2o (2 * 25ml) cleans this mixture.Then by adding the 6N HCl aqueous solution, carry out this solution of acidifying and extract with EtOAc (2 * 25ml).Via MgSO 4the dry organic phase that merges also concentrates the title compound (220mg) that is micro-yellow glue with generation in a vacuum; MS-(+)-ion: M+1=351.0.
C) [(4-benzyloxy-1-dimethylamino formyl radical-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Under agitation by ClCO 2iBu (83 μ l, 0.63mmol) is added into the 4-benzyloxy cooling with ice bath-1-dimethylamino formyl radical-isoquinoline-3-carboxylic acid (210mg, 0.6mmol), NEt 3(175 μ l, 1.25mmol) and CH 2cl 2(12ml) in mixture.After stirring 15min, add glycine benzyl hydrochloride (127mg, 0.63mmol) and separately stir again this mixture 15min, then remove ice bath.Then continue to stir again at ambient temperature 1.5h.Concentrate in a vacuum subsequently this mixture.Water (10ml) and several 6N HCl aqueous solution are added in resistates.Extract this mixture with EtOAc (15ml).Via MgSO 4dry organic phase is also concentrated to produce micro-yellow glue in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=7:3 carrys out purifying as elutriant, produces the title compound (211mg) that is slight yellow glue; MS-(+)-ion: M+1=498.1.
D) [(1-dimethylamino formyl radical-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
At H 2stir [(4-benzyloxy-1-dimethylamino formyl radical-isoquinoline 99.9-3-carbonyl)-amino]-jasmal (209mg under-atmosphere at environmental stress and temperature; 0.42mmol), the mixture 18h of Pd/C (100mg, 10 % by weight Pd), EtOAc (10ml) and MeOH (50ml).Then by Celite pad, filter this mixture.Thoroughly clean diatomite and filter cake and concentrate in a vacuum the merging organic phase with EtOAc and be the title compound (122mg) of brown solid with generation; MS-(-)-ion: M-1=316.1.
Example D-80
[(4-hydroxyl-1-methyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 1--6-phenoxy group-isoquinoline-3-carboxylic acid
Be similar to example D-77a), synthetic by the bromo-4-hydroxyl of 1--6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (example D-77a); 1h NMR (DMSO-d 6): δ=8.20 (d, 1H), 7.21-7.74 (m, 7H).
B) 4-benzyloxy-1-methyl-6-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester
Under agitation in-78 ℃ of hexanes by 2.5M n-BuLi (3.2ml, 8mmol) solution, slowly be added in anhydrous THF (100ml) solution of the bromo-4-hydroxyl of l--6-phenoxy group-isoquinoline-3-carboxylic acid (721mg, 2mmol).Dropwise add MeI (253 μ l, 4mmol) after stirring 10min again.15min is stirred again in continuation under-78 ℃, then adds water (50ml) and the 2N HCl aqueous solution (5ml).Under agitation make this mixture temperature to envrionment temperature and then be concentrated in a vacuum approximately 1/3 of its volume.The formed throw out of sucking-off, water cleans and is dry to produce brown color solid (758mg) in a vacuum.The above-mentioned brown color solid of the 738mg that under agitation refluxes, bromotoluene (1.0ml, 8mmol), K 2cO 3the mixture of (2.76g, 20mmol) and acetone (50ml) 3 days.Then concentrate in a vacuum this mixture.Water (30ml) is added in resistates and extracts this mixture with EtOAc (50ml).Via MgSO 4dry organic phase is also concentrated to produce micro-yellow oil in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=8:2 carrys out purifying as elutriant, produces the brown color solid.From MeOH, recrystallize produces the title compound (172mg) that is slight yellow solid; MS-(+)-ion: M+1=476.1.
C) 4-benzyloxy-1-methyl-6-phenoxy group-isoquinoline-3-carboxylic acid
Be similar to example D-78b), synthetic by 4-benzyloxy-1-methyl-6-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester; MS-(+)-ion: M+1=386.1.
D) [(4-benzyloxy-1-methyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Be similar to example D-78c), synthetic by 4-benzyloxy-1-methyl-6-phenoxy group-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=533.0.
E) [(4-hydroxyl-1-methyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-78d), synthetic by [(4-benzyloxy-1-methyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal; MS-(+)-ion: M+1=353.1.
Example D-81
[(4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid
Be similar to example D-77a), synthetic by the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (example D-7e); MS-(+)-ion: M+1=359.9.
B) 4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester
Be similar to example D-78a), synthetic by MeI and the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=476.1.
C) 4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid
Be similar to example D-78b), synthetic by 4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester; MS-(+)-ion: M+1=386.0.
D) [(4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Be similar to example D-78c), synthetic by 4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=533.0.
E) [(4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-78d), synthetic by [(4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal; MS-(-)-ion: M-1=351.1.
Example D-82
[(4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Stir at ambient temperature [(4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal (160mg, 0.3mmol; Example D-81d), the mixture 18h of KOH (325mg, 5mmol) and EtOH (10ml), then evaporating solvent in a vacuum.Water (5ml) is added in resistates and uses Et 2o (2 * 20ml) cleans this mixture.Then by adding the 6N HCl aqueous solution, carry out this solution of acidifying and extract with EtOAc (2 * 20ml).Via MgSO 4the dry organic phase that merges also concentrates the title compound (93mg) that is pale brown coloring agent with generation in a vacuum; MS-(+)-ion: M+1=443.0.
Example D-83
[(4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid ethyl ester
Under agitation in-78 ℃ of hexanes by 2.5M n-BuLi (3.2ml, 8mmol) solution, slowly be added in anhydrous THF (100ml) solution of the bromo-4-hydroxyl of l--7-phenoxy group-isoquinoline-3-carboxylic acid (721mg, 2mmol, example D-81a).Dropwise add MeI (253 μ l, 4mmol) after stirring 5min again.15min is stirred again in continuation under-78 ℃, then adds water (100ml) and the 2N HCl aqueous solution (5ml).Under agitation make this mixture temperature to envrionment temperature, then be concentrated in a vacuum approximately 1/2 also extracting with EtOAc (300ml) of its volume.Via MgSO 4dry organic phase is also concentrated to produce safran solid (462mg) in a vacuum.The above-mentioned safran solid of the 440mg that under agitation refluxes, EtI (0.61ml, 7.5mmol), K 2cO 3the mixture of (3.0g, 21.7mmol) and acetone (45ml) 16 days.Then concentrate in a vacuum this mixture.Water (30ml) is added in resistates and extracts this mixture with EtOAc (2 * 50ml).Via MgSO 4the dry organic phase concentrated to produce brown oil in a vacuum that merges.Use hexane on silica gel by flash column chromatography: EtOAc=8:2 carrys out purifying as elutriant, produces the title compound (34mg) that is micro-yellow oil; 1h NMR (CDCl 3): δ=8.22 (d, 1H), 7.07-7.50 (m, 7H), 4.50 (q, 2H), 4.20 (q, 2H), 2.80 (s, 3H), 1.43-1.58 (m, 6H).
B) 4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid
Be similar to example D-78b), synthetic by 4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid ethyl ester; MS-(+)-ion: M+1=324.1.
C) [(4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-tert.-butyl acetate
Be similar to example D-78c), synthetic by glycine tert-butyl hydrochloride and 4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=437.1.
D) [(4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Stir at ambient temperature the mixture 3h of [(4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-tert.-butyl acetate (14mg, 0.032mmol) and trifluoroacetic acid (2ml).Then concentrate in a vacuum this mixture and resistates is dissolved in EtOH (5ml).Evaporating mixture is the title compound (12mg) of micro-yellow solid with generation in a vacuum; MS-(-)-ion: M-1=381.1.
Example D-84
[(1-dimethylamino formyl radical-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester
Be similar to example D-79a, by the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid (example D-81a), synthesize and (use 6 equivalent ClCONMe 2, finishing to add ClCONMe 2afterwards, at-78 ℃ of lower stirred reaction mixture 75min, then add water and HCl); MS-(+)-ion: M+1=533.2.
B) 4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy group-isoquinoline-3-carboxylic acid
Be similar to example D-79b), synthetic by 4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester; MS-(-)-ion: M-1=441.1.
C) [(4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Be similar to example D-79c), synthetic by 4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy group-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=590.0.
D) [(1-dimethylamino formyl radical-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-79d), synthetic by [(4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal; MS-(+)-ion: M+1=410.0.
Example D-85
[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester
Be similar to example D-78a), synthetic by the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline-3-carboxylic acid (example D-81a); MS-(+)-ion: M+1=506.2.
B) 4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid
Be similar to example D-78b), synthetic by 4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid benzyl ester; MS-(-)-ion: M-1=414.1.
C) [(4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Be similar to example D-78c), synthetic by 4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=563.1.
D) [(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-78d), synthetic by [(4-benzyloxy-1-methoxymethyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-jasmal; MS-(+)-ion: M+1=383.0.
Example D-86
[(the p-tolyl-isoquinoline 99.9 of 4-hydroxyl-1--3-carbonyl)-amino]-acetic acid
A) the bromo-isoquinoline-3-carboxylic acid butyl ester of 4-benzyloxy-1-
Under agitation by the bromo-4-hydroxyl of 1--isoquinoline-3-carboxylic acid butyl ester (6.48g, 20mmol; Example D-28a), bromotoluene (3.6ml, 30mmol), K 2cO 3the mixture of (12.44g, 90mmol) and acetone (300ml) refluxes 2.5 days.Follow evaporating solvent in a vacuum.Water (100ml) is added in resistates and extracts this mixture with EtOAc (100ml).Via MgSO 4dry organic phase also evaporates to produce the title compound that is micro-yellow solid in a vacuum; MS-(+)-ion: M+1=414.1.
B) the p-tolyl of 4-benzyloxy-1--isoquinoline-3-carboxylic acid butyl ester
By the bromo-isoquinoline-3-carboxylic acid butyl ester of 4-benzyloxy-1-(207mg, 0.5mmol) and Pd (PPh 3) 4(23mg, 0.02mmol) is dissolved in THF (3ml) and, by this solution stirring 10min, then adds EtOH (0.5ml) solution and the Na of p-tolyl boric acid (68mg, 0.5mmol) 2cO 3the water of (106mg, 1mmol) (0.5ml) solution.Gained mixture 4h under agitation refluxes.Subsequently, concentrate in a vacuum this mixture.Water (2ml) is added in resistates and extracts this mixture with EtOAc (10ml).Via MgSO 4dry organic phase also evaporates to produce micro-yellow oil (225mg) in a vacuum.Use hexane on silica gel by flash column chromatography: EtOAc=94:6 carrys out purifying as elutriant, produces the title compound that is water white oil; MS-(+)-ion: M+1=426.2.
C) the p-tolyl of 4-hydroxyl-1--isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-78d) (EtOAc is used as to solvent), synthetic by the p-tolyl of 4-benzyloxy-1--isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=336.2.
D) [(the p-tolyl-isoquinoline 99.9 of 4-hydroxyl-1--3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by the p-tolyl of 4-hydroxyl-1--isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=337.1.
Example D-87
{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) the bromo-7-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1e), synthetic by 7-(the fluoro-phenoxy group of 4-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (example D-96e); 1h NMR (CDCl 3): δ=11.89 (s, 1H), 8.36 (d, 1H), 7.44-7.57 (m, 2H), 7.08-7.25 (m, 4H), 4.47 (q, 2H), 1.85 (m, 2H), 1.50 (m, 2H), 0.99 (t, 3H).
B) 7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
The bromo-7-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (434mg, 1mmol), Pd (PPh under agitation reflux 3) 4(116mg, 0.1mmol), trimethylboroxin (140 μ l, 1mmol), K 2cO 3the mixture 2h of (414mg, 3mmol) and Isosorbide-5-Nitrae-dioxane (8ml).Concentrate in a vacuum subsequently this mixture.Water (10ml) is added in resistates.By adding 6N HCl this mixture of acidified aqueous solution and then extracting with EtOAc (40ml).Via MgSO 4dry organic phase evaporation in a vacuum.By flash column chromatography, on silica gel, use hexane: EtOAc=94:6 to carry out the purifying resistates as elutriant, produce the title compound (229mg) of the solid that is white in color; MS-(+)-ion: M+1=370.1.
C) { [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), synthetic by 7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=371.1.
Example D-88
{ [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(4-methoxyl group-phenoxy group)-phthalonitrile
4-nitro-phthalonitrile (4.00g), 4-methoxyl group-phenol (3.46g) and the mixture of salt of wormwood (6.39g) in acetone (64ml) are heated to reflux, continue 2h.Reaction mixture is also filtered.Filtrate is concentrated and resistates is dissolved in ethyl acetate (100ml).Also then with salt solution, clean this solution with NaOH (1N, 50ml), water.Via dried over mgso organic layer, filtration concentrated to produce product (6.14g). 1H NMR(200MHz,CDCl 3)δ6.70(d,J=7.8Hz,1H),7.21(m,2H),6.96(m,4H),3.84(s,3H)。
B) 4-(4-methoxyl group-phenoxy group)-phthalic acid
Be similar to example D-1a) prepare.MS-(-)-ion: M-1=286.9.
C) [5-(4-methoxyl group-phenoxy group)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
Be similar to example D-37b) prepare. 1H NMR(200MHz,CDC1 3)δ7.74(d,J=8.6Hz,1H),7.25(m,2H),6.98(m,4H),4.40(s,2H),3.83(s,3H),3.75(s,3H)。
D) 6-and 7-(4-methoxyl group-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-21b) prepare.MS-(+)-ion: M+1=384.10.
E) 7-(4-methoxyl group-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-21c) prepare.MS-(+)-ion: M+1=384.11.
F) 1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d) prepare.MS-(+)-ion: M+1=402.0.
G) { [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g) prepare.MS-(-)-ion: M-1=400.96.
Example D-89
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) { [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-25, synthetic by { [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid; MS-(-)-ion: M-1=367.0.
Example D-90
{ [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 6-(4-methoxyl group-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
By obtaining from example D-88e) 6-and the mixture separation of 7-(4-methoxyl group-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester.MS-(+)-ion: M+1=384.1.
B) 1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d) prepare.MS-(+)-ion: M+1=402.0.
C) { [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g) prepare.MS-(+)-ion: M+1=403.0.
Example D-91
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-2a), by { [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid, prepared.MS-(-)-ion: M-1=367.0.
The compound of following instance D-92-99 is that the method by being similar to described in example D88-D91 obtains.
Example D-92
{ [1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(4-trifluoromethyl-phenoxy group)-phthalonitrile
1H NMR(200MHz,CDC1 3)δ7.74(m,2H),7.47(d,J=8.6Hz,1H),7.25(m,3H),6.87(d,J=8.9Hz,1H)。
B) 4-(4-trifluoromethyl-phenoxy group)-phthalic acid
1H NMR(200MHz,DMSO-d 6)δ8.24(d,J=9.0Hz,1H),7.75(m,3H),7.19(m,3H)。
C) [1,3-dioxy-5-(4-trifluoromethyl-phenoxy group)-1,3-dihydro-isoindole-2-yl)-methyl acetate
1H NMR(200MHz,CDC1 3)δ7.86(d,J=8.5Hz,1H),7.67(d,J=8.2Hz,2H),7.40-7.13(m,4H),4.43(s,2H),3.76 9s,3H)。
D) 6-and 7-(4-trifluoromethyl-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
The mixture of two kinds of isomer.
E) 7-(4-trifluoromethyl-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
MS-(+)-ion: M+1=422.0.
F) 1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
MS-(-)-ion: M-1=438.3.
G) { [1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
MS-(-)-ion: M-1=439.0.
Example D-93
{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
MS-(-)-ion: M-1=405.1.
Example D-94
{ [1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) Isosorbide-5-Nitrae-dihydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
MS-(+)-ion: M+1=422.0.
B) 1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
1H NMR(200MHz,CDC1 3)δ11.82(s,1H),8.30(d,J=9.0Hz,1H),7.81(d,J=2.3Hz,1H),7.67(d,J=8.6Hz,2H),7.54(dd,J=9.0,2.7Hz,1H),7.18(d,J=8.2Hz,2H),4.48(t,J=7.0Hz,2H),1.85(m,2H),1.46(m,2H),0.98(t,J=7.0Hz,3H)。
C) { [1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
MS-(-)-ion: M-1=439.1.
Example D-95
{ [4-hydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
MS-(-)-ion: M-1=405.0.
Example D-96
{ [the chloro-7-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(the fluoro-phenoxy group of 4-)-phthalonitrile
1H NMR(200MHz,CDC1 3)δ7.71(d,J=8.6Hz,1H),7.23-7.15(m,6H)。
B) 4-(the fluoro-phenoxy group of 4-)-phthalic acid
1H NMR(200MHz,CDC1 3)δ7.74(d,J=8.9Hz,1H),7.33-7.15(m,6H)。
C) [5-(the fluoro-phenoxy group of 4-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
1H NMR(200MHz,CDCl 3)δ7.80(d,J=7.4Hz,1H),7.28(m,2H),7.08(m,4H),4.41(s,2H),3.76(s,3H)。
D) 6-and 7-(the fluoro-phenoxy group of 4-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
The mixture of two kinds of isomer.
E) 7-(the fluoro-phenoxy group of 4-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
MS-(+)-ion: M+1=372.1.
F) the chloro-7-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
1H NMR(200MHz,CDCl 3)δ11.90(s,1H),8.36(d,J=9.0Hz,1H),7.56(m,2H),7.10(m,4H),4.47(t,J=7.0Hz,2H),1.85(m,2H),1.46(m,2H),0.99(t,J=7.4Hz,3H)。
G) { [the chloro-7-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
MS-(-)-ion: M-1=389.0.
Example D-97
{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
MS-(-)-ion: M-1=355.1.
Example D-98
{ [the chloro-6-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 6-(the fluoro-phenoxy group of 4-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
MS-(+)-ion: M+1=372.1.
B) the chloro-6-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
1H NMR(200MHz,CDC1 3)δ11.77(s,1H),8.25(d,J=9.0Hz,1H),7.62(d,J=2.3Hz,1H),7.50(dd,J=9.0,2.3Hz,1H),7.10(m,4H),4.46(t,J=7.0Hz,2H),1.85(m,2H),1.45(m,2H),0.98(t,J=7.4Hz,3H)。
C) { [the chloro-6-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
MS-(-)-ion: M-1=389.1.
Example D-99
{ [6-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
MS-(-)-ion: M-1=355.1.
Example D-100
{ [4-hydroxyl-7-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(pyridin-4-yl sulfenyl)-phthalonitrile
By 4-nitro-phthalonitrile (17.28g), pyridine-4-mercaptan (10.68g) and salt of wormwood (25.17g), at N, the mixture in N-dimethyl-methane amide (160ml) is heated to 85 ℃ and stir 3h.After cooling, by Celite pad, filter reaction mixture and use ethyl acetate rinse.Concentrating filtrate also produces title compound 13.29g by silica gel chromatography (with the eluent ethyl acetate of the 15-30% in methylene dichloride) purifying resistates second in a vacuum. 1H NMR(200MHz,CDC1 3)δ8.59(d,J=6.2Hz,2H),7.68(m,3H),7.24(d,J=6.3Hz,2H)。
B) 4-(pyridin-4-yl sulfenyl)-phthalic acid
Be similar to example D-1a) prepare.MS-(+)-ion: M+1=276.1.
C) [1,3-dioxy-5-(pyridin-4-yl sulfenyl)-1,3-dihydro-isoindole-2-yl)-butylacetate
The solid mixture of 4-(pyridin-4-yl sulfenyl)-phthalic acid (11.40g) and the positive butyl ester hydrochloride of glycine (6.95g) is heated to 20min until the bubble evaporation stops in oil bath (250 ℃) under effectively stirring.After cooling, it is divided between ethyl acetate (300ml) and saturated sodium bicarbonate aqueous solution (150ml) molten.Separates two is also used ethyl acetate (300ml) aqueous layer extracted.With salt solution cleaning merging organic layer, via dried over mgso, filtration concentrated to produce title compound 10.70g.MS-(+)-ion: M+1=371.2.
D) 6-and 7-(pyridin-4-yl sulfenyl)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-21b) prepare.
E) 6-and 7-(pyridin-4-yl sulfenyl)-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d) prepare.MS-(+)-ion: M+1=389.1.
F) 6-and 7-(pyridin-4-yl sulfenyl)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1f) prepare.By silica gel chromatography (the 50%-80% ethyl acetate in methylene dichloride) purification of crude product to produce 7-(pyridin-4-yl sulfenyl)-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-100A) (MS-(+)-ion: M+1=355.04) and 6-(pyridin-4-yl sulfenyl)-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-100B) (MS-(+)-ion: M+1=355.13).
G) { [4-hydroxyl-7-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g) prepare.MS-(+)-ion: M+1=356.1.
Example D-101
{ [4-hydroxyl-6-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), by 6-(pyridin-4-yl sulfenyl)-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-100B), prepared.MS-(+)-ion: M+1=356.1.
Example D-102
[(7-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 7-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
At room temperature by 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (300mg) and
Figure BDA00002247957201391
(Du Pont's speciality chemical (Dupont Specialty Chemicals), Willmington, DE, USA) (366mg) slurry mixture in (3/2) methanol/water (5ml) stirs 4h.Reaction mixture is divided between methylene dichloride and saturated sodium bicarbonate aqueous solution molten.Clean organic layer with saturated sodium bicarbonate aqueous solution and water.Via dried over mgso filtration.Filtrate is concentrated and pass through silica gel chromatography (0%-50% ethyl acetate in methylene dichloride) purifying resistates to produce (50mg) (MS-(+)-ion: M+1=370.1) and (90mg) (MS-(+)-ion: M+1=386.1) of 7-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-102B) of title compound 7-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-102A).
B) [(7-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), by 7-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-102A), prepared.MS-(+)-ion: M+1=371.1.
Example D-103
[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), by 7-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-102B), prepared.MS-(+)-ion: M+1=387.1.
Example D-104
[(6-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 6-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example B-18a), by 4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester, prepared.Separate two kinds of compounds by chromatography: title compound 6-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-104A) (MS-(+)-ion: M+1=370.1) with 6-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-104B) (MS-(+)-ion: M+1=386.1).
B) [(6-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), by 6-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-104A), prepared.MS-(-)-ion: M-1=369.0.
Example D-105
[(6-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), by 6-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-104B), prepared.MS-(-)-ion: M-1=385.1.
Example D-106
[(6-amino-4-hydroxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) (5-nitro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate
Salt of wormwood (57.8g) is added into to 5-nitro-isoindole-1, in 3-diketone (26.2g) and the solution mixture of ethyl bromoacetate (25.1g) in acetone (500ml).By gained mixture reflux (18h) whole night.After cooling, filter reaction mixture and use ethyl acetate rinse.Filtrate is concentrated and by resistates wet-milling in ether (200ml).Collect solid and rinse with ether.Dry to produce title compound 231.9g in a vacuum. 1H NMR(200MHz,CDC1 3)δ8.69(m,2H),8.07(d,J=8.2Hz,1H),4.48(s,2H),4.24(q,J=7.0Hz,2H),1.30(t,J=7.0Hz,3H)。
B) (5-amino-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate
10% palladium/C (50% is wet) solid (2.0g) is added in (5-nitro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-solution mixture of ethyl acetate (10.0g) in Glacial acetic acid (150ml).At H 2(storage pressure) lower room temperature vigorous stirring is (18h) whole night.Leach catalyzer and use dichloromethane rinse by Celite pad.Concentrating filtrate is to produce title compound (7.0g). 1H NMR(200MHz,CDCl 3)δ7.59(d,J=8.2Hz,1H),7.02(d,J=2.0Hz,1H),6.81(dd,J=8.2,2.0Hz,1H),4.38(br S,2H),4.36(s,2H),4.20(q,J=7.0Hz,2H),1.27(t,J=7.0Hz,3H)。
C) [5-(diphenylmethylene-amino)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-ethyl acetate
Titanium tetrachloride slowly is added in (5-amino-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate (3.48g), benzophenone (2.81g) and the mixture of DABCO (4.72g) in chlorobenzene (112mg).The mixture of gained is heated to reflux, continues 2.5h.After cooling, by Celite pad, filter reaction mixture and use ethyl acetate rinse.Concentrating filtrate also passes through silica gel chromatography (the 25%-40% ethyl acetate in hexane) purifying resistates to produce title compound (3.03g).MS-(+)-ion: M+1=413.3.
D) 6-and 7-(diphenylmethylene-amino)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-21b) prepare.MS-(+)-ion: M+1=441.2.
E) 6-and 7-amino-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d) prepare.By silica gel chromatography (with 50% eluent ethyl acetate in hexane) purification of crude product to produce title compound.MS-(+)-ion: M+1=295.1.
F) 6-and 7-amino-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester
10%Pd/C (50% wet) (110mg) be added in ethyl acetate (5ml) solution of 6-and 7-amino-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (220mg) and then add ammonium formiate (471mg).The mixture of gained is heated to reflux, continues 0.5h.After cooling, with ethyl acetate (50ml) diluted reaction mixture filtration.Concentrating filtrate is to produce title compound (182mg).MS-(+)-ion: M+1=261.2.
G) 6-and 7-amino-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
At room temperature by 6-and 7-amino-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (180mg), 4-methoxyl group-benzene sulfonyl chloride (145mg) and triethylamine (85mg), the mixture in methylene dichloride (7ml) stirs 18h.Water (20ml) is 4 by its dilution and by 0.1N HCl acidified aqueous solution to pH value.Separate two-phase and use the dichloromethane extraction water layer.Clean and merge organic phase with salt solution, via dried over mgso, filtration concentrated.Produce two kinds of products by silica gel chromatography (the 55%-80% ethyl acetate in hexane) purification of crude product: 7-amino-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (Compound D-106A) is (MS-(+)-ion: M+1=431.1) and (70mg) (MS-(+)-ion: M+1=431.1) of 6-amino-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (Compound D-106B) (79mg).
H) [(6-amino-4-hydroxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), by 6-amino-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (Compound D-106B) preparation.MS-(-)-ion: M-1=260.1.
Example D-107
{ [4-hydroxyl-7-(4-methoxyl group-phenylsulfonamido)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 7-[(N, N-bis--4-methoxyl group-benzenesulfonyl) amino]-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
In microwave reactor by the 7-amino-4-in sealed vessel (4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (Compound D-106A) (75mg), 4-methoxyl group-benzene sulfonyl chloride (140mg) and the mixture of triethylamine (76mg) in methylene dichloride (2ml) be heated to 120 ℃, continues 10min.After cooling, concentrated reaction mixture also passes through silica gel chromatography (with the 5%-10% eluent ethyl acetate in methylene dichloride) purifying to produce title compound (68mg).MS-(+)-ion: M+1=770.99.
B) { [4-hydroxyl-7-(4-methoxyl group-phenylsulfonamido)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
The heating of the mixture in 0.5N sodium methylate/methyl alcohol (2.7ml) by the above-mentioned ester (68mg) in sealed vessel and glycine (86mg) in microwave reactor (150 ℃, 17min).After cooling, concentrated reaction mixture.Resistates is dissolved in water (10ml) and by ethyl acetate (15ml) and extracts.Water layer is acidified to pH=4 and extracts by ethyl acetate (2 * 50ml) by the 2N HCl aqueous solution.Clean and merge organic layer with salt solution, via dried over mgso, filtration concentrated.With methyl alcohol and (1/1) ethyl acetate/hexane wet-milling crude product, produce title compound 14mg.MS-(-)-ion: M-1=430.
Example D-108
{ [4-hydroxyl 7-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 6-and 7-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
(18h) stirs 6-and 7-amino-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (160mg) and the mixture of phenylcarbimide (73mg) in methylene dichloride (4ml) concentrated at room temperature whole night.With (1/1) ethyl acetate/dichloromethane (8ml) wet-milling resistates.Collect insoluble solids and rinse with methylene dichloride (5ml) by filtration.Dry to produce (82mg) (MS-(+)-ion: M+1=380.18) of 7-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-108A).Filtrate is concentrated and pass through silica gel chromatography purifying resistates and then from methyl alcohol recrystallize to produce (82mg) (MS-(+)-ion: M+1=380.15) of 6-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-108B).
B) { [4-hydroxyl 7-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), by 7-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-108A) preparation.MS-(-)-ion: M-1=379.07.
Example D-109
{ [4-hydroxyl-6-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) { [4-hydroxyl-6-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), by 7-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-108B) preparation.MS-(-)-ion: M-1=379.08.
Example D-110
[(4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be prepared as follows title compound: the 1.2ml benzenethiol is added into to 250mg[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (United States Patent (USP) 6,093,730, be disclosed as N-((1-chloro-4-hydroxyl isoquinoline 99.9-3-yl) carbonyl) glycine) be dissolved in the solution in the 1ml1-N-methyl-2-2-pyrrolidone N-.Heat 16h by under in 130 to 150 ℃ of this solution in sealed tube.Solution is concentrated under vacuum.From methyl alcohol, crystallization gained resistates is to obtain 91mg brown color solid; MS (-) m/z353.07 (M-1).
Example D-111
{ [1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Under the condition that is similar to example D-110, by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (United States Patent (USP) 6,093,730) and 4-chlorobenzene mercaptan, prepare title compound; MS (+) m/z389.06 (M+1).
Example D-112
[(the p-tolyl sulfenyl-isoquinoline 99.9 of 4-hydroxyl-1--3-carbonyl)-amino]-acetic acid
Under the condition that is similar to example D-110, by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (United States Patent (USP) 6,093,730) and 4-methylbenzene mercaptan, prepare title compound; MS (-) m/z367.09 (M-1).
Example D-113
[(4-hydroxyl-1-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Under the condition that is similar to example D-110, by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (United States Patent (USP) 6,093,730) and 2-mercaptopyridine, prepare title compound.Carry out purifying final product with the 3-15% methyl alcohol in methylene dichloride and 0.5% acetic acid gradient elution product by column chromatography on silica gel; MS (-) m/z354.10 (M-1).
Example D-114
{ [4-hydroxyl-1-(3-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Under the condition that is similar to example D-110, by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (United States Patent (USP) 6,093,730) and 3-anisole mercaptan, prepare title compound.Use hexane that final product is precipitated from the solution of ethyl acetate; MS (-) m/z385.12 (M-1).
Example D-115
{ [4-hydroxyl-1-(2-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Under the condition that is similar to example D-110, by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (United States Patent (USP) 6,093,730) and 2-anisole mercaptan, prepare title compound.Make final product crystallization from methylene dichloride; MS (-) m/z383.08 (M-1).
Example D-116
{ [4-hydroxyl-1-(naphthalene-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Under the condition that is similar to example D-110, by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (United States Patent (USP) 6,093,730) and 2-naphthyl mercaptan, prepare title compound.By with methyl alcohol wet-milling crude product, also with the methylene dichloride wet-milling, carrying out the purifying final product 2 times 2 times; MS (+) m/z405.08 (M+1).
Example D-117
[(1-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be prepared as follows title compound: by 50mg[(4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (example D-110) is dissolved in 0.3ml1-N-methyl-2-2-pyrrolidone N-and 0.7ml methylene dichloride.Solution is cooled to 0 ℃ and add 26mg75%3-chlorine peroxybenzoic acid.At room temperature stir this solution 2 hours, then concentrated under high vacuum.With ethyl acetate wet-milling gained resistates, obtain the be white in color product of solid of 32mg; MS (-) m/z369.08 (M-1).
Example D-118
[(1-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be prepared as follows title compound: by 50mg[(4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid (example D-110) is dissolved in 0.1ml1-N-methyl-2-2-pyrrolidone N-and 0.7ml methylene dichloride.72mg75%3-chlorine peroxybenzoic acid is added so far in solution.At room temperature by this solution stirring 6 hours.Mixture is divided between ethyl acetate and water molten.Via organic part of anhydrous magnesium sulfate drying, and be concentrated into resistates.With ethyl acetate wet-milling gained resistates, obtain the be white in color product of solid of 28mg; MS (-) m/z385.09 (M-1).
Example D-119
{ [4-hydroxyl-7-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(pyridine-2-base sulfenyl)-phthalonitrile
Be suspended in 250ml acetone by 10g2-mercaptopyridine, 14.2g4-nitrophthalonitrile and 22.6g salt of wormwood and heat 4 hours under reflux temperature.Filter this solution by Celite pad and water conservancy diversion glass filter and remove residual solid.Solution is concentrated into to thick resistates and carrys out purifying with the 0-10% ethyl acetate gradient elution product in methylene dichloride by column chromatography on silica gel.Reclaim the 6.4g product; 1h NMR (200Mz, CDC1 3) δ=8.49-8.53 (m, 1H), 7.84-7.83 (dd, 1H), 7.76-7.71 (m, 2H), 7.68-7.64 (dd, 1H), 7.40-7.36 (dt, 1H), 7.27-7.20 (m, 1H).
B) { [4-hydroxyl-7-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1, by 4-(pyridine-2-base sulfenyl)-phthalonitrile, prepare title compound; MS (+): m/z356.01 (M+1).
Example D-120
{ [4-hydroxyl-6-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-119, by 4-(pyridine-2-base sulfenyl)-phthalonitrile, prepare title compound; MS (+): m/z356.02 (M+1).
Example D-121
[(1-chloro-4-hydroxyl-6,7-bis-phenoxy groups-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4,5-bis-phenoxy group phthalonitriles
By 5.0g4,5-dichloro phthalonitrile is dissolved in 50ml DMSO and adds 14.3g phenol and solution is heated to 90 ℃.Within every 5 minutes, add 6.9g salt of wormwood until altogether add 55.2g.Stir this compound 30min at 90 ℃, follow cooling and injection 500ml frozen water.Collect the gained solid sediment and from methyl alcohol crystallization the 3.6g product is provided; 1h NMR (200Mz, CDC1 3) δ=7.49-7.38 (m, 4H), 7.32-7.25 (m, 2H), 7.15 (s, 2H) 5(7.10-7.02 m, 4H).
B) [(1-chloro-4-hydroxyl-6,7-bis-phenoxy groups-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-7a-d and example D-9a-b, by 4,5-, bis-phenoxy group phthalonitrile synthesising title compounds; MS (+): m/z465.05 (M+1).
Example D-122
[(4-hydroxyl-6,7-bis-phenoxy groups-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-7, by 4,5-, bis-phenoxy group phthalonitriles (example D-121a) synthesising title compound; MS (+): m/z431.07 (M+1).
Example D-123
(4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy group]-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid
A) 1-chloro-4-hydroxyl-6-(4-nitro-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
200mg1-chloro-4-hydroxyl-6-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (example D-10a) is dissolved in the 3ml vitriol oil.Reaction mixture is cooled to-20 ℃ and 60mg saltpetre slowly is added in stirred solution.Reaction is remained between-10 to-20 ℃, stir 15min simultaneously, and be injected in frozen water.By ethyl acetate, water mixture is extracted 2 times.Clean organic part with saturated bicarbonate and salt brine solution successively, via anhydrous magnesium sulfate drying and be evaporated to resistates.Then use methyl alcohol wet-milling gained solid with the ethyl acetate wet-milling, produce the 103mg white solid; MS (+): m/z417.07 (M+1).
B) 6-(4-amino-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
100mg1-chloro-4-hydroxyl-6-(4-nitro-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester is added in 3mlTHF and 3ml methyl alcohol.20mg sodium acetate and 25mg10% palladium on carbon are added so far in mixture, and stirring reaction is placed under nitrogen atmosphere (ball) whole night.Filter gained solution and be concentrated into resistates by Celite pad.Carry out purification of crude material with the 0-20% ethyl acetate gradient elution product in methylene dichloride by column chromatography on silica gel, produce the 59mg product; MS (-): m/z351.27 (M-1).
C) 4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy group]-the isoquinoline-3-carboxylic acid butyl ester
By 58mg6-(4-amino-phenoxy group)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester, 15.8mg pyridine and 34mg p-toluenesulfonyl chloride are dissolved in the 0.3ml anhydrous methylene chloride.Stir this mixture 16 hours, and then divide molten between 0.25N HCl and ethyl acetate.Water, saturated bicarbonate and salt brine solution clean organic part successively, then via anhydrous sodium sulfate drying, and are concentrated into the thick solid of 84mg.Produce the 42mg white solid with this thick material of ethyl acetate wet-milling; 1h NMR (200Mz, CDC1 3) δ=11.7 (s, lH), 8.72 (d, 1H), 7.93-7.88 (d, 1H), 7.69-7.65 (d, 2H), 7.56-7.54 (m, 2H), (7.44-7.39 dd, 1H), 7.27-7.13 (m, 5H), (7.00-6.96 d, 2H), 4.46 (t, 2H), (2.4 s, 3H), 1.87-1.82 (quintet, 2H), (1.48-1.40 quint, 2H), 1.00-0.95 (t, 3H).
D) (4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy group]-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid
By 42mg4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy group]-isoquinoline-3-carboxylic acid butyl ester and 70mg glycine be added in the methanol solution of 1.85ml0.5M sodium methylate.The gained mixture is heated to 24h at reflux temperature, and then be cooled to room temperature.Reactant is injected to the 0.2N HCl aqueous solution and then is extracted with ethyl acetate 3 times.Via organic part of anhydrous sodium sulfate drying, and be concentrated into the 41mg white solid; MS (+): m/z508.10 (M+1).
Example D-124
{ [4-hydroxyl-7-(4-nitro-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-hydroxyl-7-(4-nitro-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
2.0g4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (example D-7f) is dissolved in 15ml TFA.The 0.375ml nitrosonitric acid is slowly added so far in solution, and at room temperature stir the gained mixture 7 hours.Concentrated reaction mixture under vacuum, and carry out purifying gained resistates with the 0-20% eluent ethyl acetate in methylene dichloride by column chromatography on silica gel.The crude product obtained with the methyl alcohol wet-milling produces the 1.0g white solid; MS (+): m/z383.01 (M+1).
B) { [4-hydroxyl-7-(4-nitro-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-1g), by 4-hydroxyl-7-(4-nitro-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester synthesising title compound; MS (-): m/z382.06 (M-1).
Example D-125
[(4-sulfydryl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-dimethyl thiocarbamyl oxygen base-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
By the 578mg dimethyl sulphide, for chloroformamide and 1.5g1,4-diaza-bicyclo [2.2.2] octane is added into 1.5g4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (example D-7f) and is dissolved in the solution of 6.3ml dry DMF.At room temperature stir whole night this mixture.Mixture is injected to 30ml1N HCl and divides 3 extractions by the 30ml ethyl acetate.Water and salt solution clean organic part, via anhydrous sodium sulfate drying concentrated to produce the 1.9g product; MS (+) m/z425.27 (M+1).
B) 4-dimethylamino formyl radical sulfenyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
The solution that 1.9g4-dimethyl thiocarbamyl oxygen base-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is dissolved in to the 22ml phenyl ether is heated to 190 ℃, continues 2 hours.Under vacuum, concentrated this solution is to produce thick resistates, and it carrys out purifying with this product of 30-80% ethyl acetate gradient elution in hexane by column chromatography on silica gel, produces 1.73g; MS (+) m/z425.07 (M+1).
C) 4-sulfydryl-7-phenoxy group-isoquinoline-3-carboxylic acid methyl esters
460mg4-dimethylamino formyl radical sulfenyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester is added in the methanol solution of 6.5ml0.5N sodium methylate.Gained solution is heated to 50-60 ℃, continues 8 hours, be cooled to room temperature and dilute with 10ml water and 7.0ml1N HCl.Filter by (medium) porous Bu Shi filter funnel the yellow mercury oxide that this solution is collected gained, produce the 307mg product; MS (+) m/z312.08 (M+1).
D) [(4-sulfydryl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
75mg4-sulfydryl-7-phenoxy group-isoquinoline-3-carboxylic acid methyl esters and 181mg glycine are added in the methanol solution of 4.3ml0.5M sodium methylate.Use CEM Discover microwave reactor (City, State) that this mixture is heated to 150 ℃, continue 10min.Cooling gained solution also produces yellow mercury oxide with the acidifying of 1N HCl solution.Filter this solution by (medium) porous Bu Shi filter funnel and carry out the collecting precipitation thing, and produce the 68mg product with the methyl alcohol wet-milling; MS (-): m/z353.02 (M-1).
Example D-126
[(4-sulfydryl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-hydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester
Under the condition that is similar to example D-7a-f, by 4-trifluoromethyl phthalic acid, prepare title compound; MS (+) m/z314.1 (M+1).
B) [(4-sulfydryl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Under the condition that is similar to example D-125, by 4-hydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester, prepare title compound; MS (-) m/z328.33 (M-1).
Example D-127
{ [7-(4-phenylsulfonamido-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-123b-d, in step c, with benzene sulfonyl chloride, replace p-toluenesulfonyl chloride, by 4-hydroxyl-7-(4-nitro-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester (example D-124a) synthesising title compound; MS (+): m/z494.09 (M+1).
Example D-128
{ [4-hydroxyl-7-(4-methanesulfonamido-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-123b-d, in step c, with benzene sulfonyl chloride, replace p-toluenesulfonyl chloride, by 4-hydroxyl-7-(4-nitro-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester (example D-124a) synthesising title compound; MS (-): m/z430.03 (M-1).
Example D-129
{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(the chloro-phenoxy group of 4-)-phthalonitrile
Be similar to example D-88a) prepare. 1H NMR(200MHz,DMSO)δ8.09(d,J=9Hz,1H),7.83(d,J=2.6,1H),7.53(d,J=8.6Hz,2H),7.42(dd,J=2.8,8.6Hz,1H),7.24(d,J=8.6,2H)。
B) 4-(the chloro-phenoxy group of 4-)-phthalic acid
Be similar to example D-1a) prepare.MS-(-)-ion: M-1=291.0.
C) [5-(the chloro-phenoxy group of 4-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
Be similar to example D-100c) prepare. 1H NMR(200MHz,DMSO)δ7.48(d,J=8.6Hz,1H),7.59(d,J=9.0Hz,2H),7.46(m,2H),7.29(d,J=9.0Hz,2H),4.46(s,2H),4.16(t,J=6.2Hz,2H),1.61(m,2H),1.38(m,2H),0.92(t,J=7.0Hz,3H)。
D) 6-and 7-(the chloro-phenoxy group of 4-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=386.1.
E) the chloro-6-of 1-and 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=404.2.
F) 6-and 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1f) prepare.Separate two kinds of isomer and produce 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-l29A): MS-(-)-ion: M-1=370.3 and 6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-l29B): MS-(-)-ion: M-1=370.3.
G) { [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-129A), started to prepare.MS-(-)-ion: M-1=371.0.
Example D-130
{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) { [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-129B), started to prepare.MS-(-)-ion: M-1=371.1.
Example D-131
{ [6-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 4-(the fluoro-phenoxy group of 3,4-bis-)-phthalonitrile
Be similar to example D-88a) prepare. 1H NMR(200MHz,DMSO)δ8.14(d,J=9Hz,1H)5 7.95(d,J=2.6,1H),7.56(dd,J=2.6,8.6Hz,1H),7.19(dt,J=2.4,9.2Hz,1H),7.04(m,2H)。
B) 4-(the fluoro-5-methoxyl group-phenoxy group of 3-)-phthalic acid
Be similar to example D-1a) prepare.In hydrolysis, one fluorine-based by methoxy substitution.MS-(-)-ion: M-1=305.0.
C) [5-(the fluoro-5-methoxyl group-phenoxy group of 3-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
Be similar to example D-100c) prepare. 1H NMR(200MHz,DMSO)δ7.93(d,J=8.6Hz,1H),7.43(m,2H),6.79-6.63(m,3H),4.41(s,2H),4.10(t,J=6.2,2H),1.54(m,2H),1.30(m,2H),0.86(t,J=7.0,3H)。
D) 6-and 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=400.1.
E) the chloro-6-of 1-and 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=418.3.
F) 6-and 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
By 10%Pd/C, (50% is wet, 70mg) is added in ethyl acetate (3ml) solution of the chloro-6-of l-and 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (176mg) and then adds ammonium formiate (264mg).The mixture of gained is heated to reflux, continues 0.5h.After cooling, use the ethyl acetate diluted reaction mixture and filter by Celite pad.Concentrating filtrate also separates to produce 64mg7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-131A) and 74mg6-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-131B) by chromatography: 1h NMR (200MHz, CD 3oD) δ 8.73 (s, 1H) 5 8.15 (d, J=9.0Hz, 1H), (7.71 s, 1H), 7.59 (m, 1H), (6.65-6.47 m, 3H), 4.49 (t, J=6.6Hz, 2H), 3.81 (s, 3H), 1.87 (m, 2H), 1.56 (m, 2H), (1.03 t, J=7.4,3H).
G) { [6-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 6-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-131B), started to prepare.MS-(-)-ion: M-1=385.1.
Example D-132
{ [7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-131A), started to prepare.MS-(-)-ion: M-1=385.1.
Example D-133
{ [7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 5-(the fluoro-phenoxy group of 3,4-bis-)-isoindole-1, the 3-diketone
By 3,4-difluorophenol (650mg) and benzene azeotropic and be dissolved in the methanol solution of sodium methylate (0.5M, 10ml).Then under nitrogen, decompression removes methyl alcohol.In mixture before then dry DMF (10ml) solution of 4-nitro phthalic imidine (769mg) being added into.The mixture of gained is at refluxed under nitrogen 23h.Cooling and the interpolation 80ml water by reaction.Filter the throw out of gained, water cleans (4 times) the dry title compound with generation 685mg.MS-(-)-ion: M-1=274.3.
B) [5-(the fluoro-phenoxy group of 3,4-bis-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
By 5-(the fluoro-phenoxy group of 3,4-bis-)-isoindole-1,3-diketone (680mg), salt of wormwood (1g), propione (20ml) and methyl bromoacetate (295 μ l) are added into penstock.The mixture of gained is heated to 105 ℃, continues 17h.With 20ml water diluting reaction thing and be extracted with ethyl acetate (2 times).Dry organic layer is also concentrated.By silica gel chromatography, use 4:1 hexane/ethyl acetate and 3:1 hexane/ethyl acetate purified mixture to produce the 657mg title compound: 1h NMR (200MHz, DMSO) δ 7.95 (d, J=9.0Hz, 1H), 7.64-7.41 (m, 4H), 7.15-7.08 (m, 1H), 4.44 (s, 2H), 3.70 (s, 3H).
C) 6-and 7-(the fluoro-phenoxy group of 3,4-bis-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=388.1.
D) the chloro-6-of 1-and 7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d) prepare.The mixture of two kinds of isomer directly continues on for next step.
E) 6-and 7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-131f) prepare.Separate two kinds of isomer and produce 7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-133A) and 6-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound 133B).
F) { [7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-133A), started to prepare.MS-(-)-ion: M-1=373.2.
Example D-134
{ [6-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) { [6-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 6-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-133B), started to prepare.MS-(-)-ion: M-1=373.2.
Example D-135
{ [4-hydroxyl-7-(4-trifluoromethoxy-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 5-(4-trifluoromethoxy-phenoxy group)-isoindole-1, the 3-diketone
Be similar to example D-133a) prepare.MS-(-)-ion: M-1=322.3.
B) [1,3-dioxy-5-(4-trifluoromethoxy-phenoxy group)-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to example D-133b), reflux and prepare whole night. 1H NMR(200MHz,CDC1 3)δ7.83(d,J=8.6,1H),7.34-7.24(m,4H),7.09(d,J=8.6,2H),4.42(s,2H),3.76(s,3H)。
C) Isosorbide-5-Nitrae-dihydroxyl-6-and 7-(3-trifluoromethoxy-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=436.2.
D) 1-chloro-4-hydroxyl-6-and 7-(3-trifluoromethoxy-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d), use microwave reactor with toluene as solvent and use 1.5 equivalent POCl 3prepare.The mixture of two kinds of isomer is directly continued on for to next step.
E) 4-hydroxyl-6-and 7-(3-trifluoromethoxy-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-131f) prepare.Separate two kinds of isomer and produce 4-hydroxyl-7-(3-trifluoromethoxy-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester (Compound D-135A): MS-(+)-ion: M+1=422.2 and 4-hydroxyl-6-(3-trifluoromethoxy-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester (Compound D-135B): MS-(-)-ion: M-1=420.6.
F) { [4-hydroxyl-7-(4-trifluoromethoxy-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 4-hydroxyl-7-(3-trifluoromethoxy-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester (Compound D-135A), started to prepare.MS-(-)-ion: M-1=421.2.
Example D-136
{ [4-hydroxyl-6-(4-trifluoromethoxy-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 4-hydroxyl-6-(3-trifluoromethoxy-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester (Compound D-135B), started to prepare.MS-(-)-ion: M-1=421.1.
Example D-137
{ [7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) [5-(the fluoro-phenoxy group of 3,5-bis-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-ethyl acetate
By (5-nitro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate (2g), 3,5-difluorophenol (1.12g), salt of wormwood (1.39g) and N,N-DIMETHYLACETAMIDE (27ml) are added in 80ml microwave reaction container.Make the gained mixture react 10min in 100 ℃ in microwave.Add water (280ml) and filter the gained throw out, cleaning and drying with water.Be further purified and produce the 0.94g title compound by silica gel chromatography. 1H NMR(200MHz,CDC1 3)δ7.86(d,J=8.2Hz,1H),7.41-7.31(m,2H),6.67-6.57(m,3H),4.41(s,2H),4.22(q,J=7.1Hz,2H),1.29(t,J=7.0Hz,3H)。
B) 6-and 7-(the fluoro-phenoxy group of 3,5-bis-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) prepare title product.Produce the mixture of two kinds of isomer.MS-(+)-ion: M+1=390.1.
C) the chloro-6-of 1-and 7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-43d) prepare, just reaction is carried out 10min in 135 ℃ in microwave reactor, uses the POCl of toluene as solvent and 1.5 equivalents 3.Produce the mixture of two kinds of isomer.MS-(-)-ion: M-1=406.2.
D) 6-and 7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-131f) prepare.Separate two kinds of isomer and produce 7-(3, the fluoro-phenoxy group of 5-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-137A): MS-(-)-ion: M-1=372.2 and 6-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-137B): MS-(+)-ion: M+1=374.1.
E) { [7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-137A), started to prepare.MS-(-)-ion: M-1=373.1.
Example D-138
{ [6-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) { [6-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 6-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-137B), started to prepare.MS-(-)-ion: M-1=373.1.
Example D-139
(7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid
A) 5-[4-(the fluoro-phenoxy group of 4-)-phenoxy group] and-1,3-dioxy-1,3-dihydro-isoindole-2-yl }-ethyl acetate
Be similar to example D-137a), by making (5-nitro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate and 4-(the fluoro-phenoxy group of 4-)-phenol reactant, prepare. 1H NMR(200MHz,CDC1 3)δ7.80(d,J=8.0Hz,1H),7.31(m,2H),7.06-7.01(m,8H),4.39(s,2H),4.21(q,J-7.2,2H),1.30(t,J=7.3,3H)。
B) 6-and 7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) prepare.Produce the mixture of two kinds of isomer.MS-(-)-ion: M-1=462.1.
C) the chloro-6-of 1-and 7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-137c) prepare.Produce the mixture of two kinds of isomer.MS-(+)-ion: M+1=482.1.
D) 6-and 7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-131f) prepare.Separate two kinds of isomer and produce 7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-139A): MS-(+)-ion: M+1=448.1 and 6-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-139B): MS-(+)-ion: M+1=448.2.
E) (7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid
Be similar to example D-37e), by 7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-139A) starts to prepare title product.MS-(-)-ion: M-1=447.1.
Example D-140
(6-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid
A) (7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid
Be similar to example D-37e), by 6-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-139B) starts to prepare title product.MS-(-)-ion: M-1=447.1.
Example D-141
{ [7-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 5-(the fluoro-phenoxy group of the fluoro-4-of 3-)-isoindole-1, the 3-diketone
Be similar to example D-133a) prepare title product.MS-(-)-ion: M-1=290.5.
B) [5-(3-fluoro--the fluoro-phenoxy group of 4-)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
Be similar to example D-133b) prepare title product. 1H NMR(200MHz,CDC1 3)δ7.83(d,J=8.2Hz,1H),7.32-7.14(m,4H),6.99(m,1H),4.42(s,2H),3.77(s,3H)。
C) 6-and 7-(the fluoro-phenoxy group of the chloro-4-of 3-)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=404.1.
D) the chloro-7-of 1-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-137c) prepare.The mixture of two kinds of isomer.MS-(-)-ion: M-1=422.2.
E) 6-and 7-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1f) prepare.Separate two kinds of isomer and produce 7-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-141A): 1h NMR (200MHz, CDC1 3) δ 11.91 (s, 1H), 8.64 (s, 1H), 8.38 (d, J=9.0Hz, 1H), 7.46 (d, J=9.4,1H), 7.24-7.16 (m, 3H), 7.04-6.98 (m, 1H), 4.50 (t, J=6.8,2H), (1.88 q, J=7.2,2H), 1.58-1.40 (m, 2H), 0.99 (t, J=7.2,3H); And 6-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-141B).MS-(+)-ion: M+1=390.1.
F) { [7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 7-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-141A), started to prepare.MS-(-)-ion: M-1=389.0.
Example D-142
{ [6-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) { [6-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), by 6-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-141B), started to prepare.MS-(-)-ion: M-1=389.0.
Example D-143
{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 6-and 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-87b), by the mixture of the chloro-6-of 1-and 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (preparing in example D-129e), started to prepare.But, omit and adjust the pH value.Separate two kinds of isomer and produce 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (compound of example D-143a): MS-(+)-ion, M-1=386.1 and 6-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (compound of example D-143b): MS-(+)-ion, M-1=386.1.
B) { [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), start and prepare whole night in 90 ℃ of reactions in penstock by 7-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (compound of example D-143a).MS-(-)-ion M-1=385.0.
Example D-144
{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) { [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), start and prepare whole night in 90 ℃ of reactions in penstock by 6-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (compound of example D-143b).MS-(-)-ion M-1=385.0.
Example D-145
{ [7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A) 6-and 7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-87b), by the mixture of the chloro-6-of 1-and 7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (preparing in example D-137c), started to prepare.The slightly different adjustment that have been to omit the pH value of handling procedure.Separate two kinds of isomer and produce 7-(3, the fluoro-phenoxy group of 5-bis-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-145a1): MS-(-)-ion, M-1=386.3 and 6-(3, the fluoro-phenoxy group of 5-bis-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-145a2): MS-(-)-ion, M-1=386.3.
B) { [7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-37e), start and prepare whole night in 90 ℃ of reactions in penstock by 7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-145a1).MS-(-)-ion M-1=387.1.
Example D-146
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A.6-and the bromo-4-hydroxyl of 7-(4-methoxyl group-phenoxy group)-1--isoquinoline-3-carboxylic acid butyl ester
In microwave reactor (sealed tube) in 130 ℃ of heating 6-and 7-(4-methoxyl group-phenoxy group)-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl esters (Compound D-88d) (3.0g) and the mixture 15min of bromine phosphorus oxide (3.4g) in dry toluene (40ml).After cooling, concentrated reaction mixture also adds saturated sodium bicarbonate aqueous solution (100ml).Stir 20min and then extract by ethyl acetate (2 * 100ml).To merge organic layer water, salt solution cleaning, via dried over mgso, filtration concentrated to produce title compound (3.1g).MS-(+)-ion M+1=446.05,448.05.
B.6-and 7-(4-methoxyl group-phenoxy group)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
In microwave reactor (sealed tube) in 120 ℃ of heating 6-and the bromo-4-hydroxyl of 7-(4-methoxyl group-phenoxy group)-1--isoquinoline-3-carboxylic acid butyl esters (232mg), Pd (PPh 3) 4(60mg), trimethylboroxin (65mg) and the mixture 10min of salt of wormwood (216mg) in dioxane (4ml).After cooling, water (15ml) diluted reaction mixture.Be acidified to pH=4 with 2N HCl.Be extracted with ethyl acetate.Clean organic layer with salt solution, via dried over mgso filtration.Concentrating filtrate also separates to produce 7-(4-methoxyl group-phenoxy group)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (35mg) (Compound D-146b1) (MS-(+)-ion M+1=382.18) and 6-(4-methoxyl group-phenoxy group)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (61mg) (Compound D-146b2) (MS-(+)-ion M+1=382.16) by silica gel chromatography (with 25% to 50% eluent ethyl acetate in hexane).
C) { [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-107b), by 7-(4-methoxyl group-phenoxy group)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-146b1) preparation (120 ℃ of microwave reaction temperature, reaction times 10min).MS-(-)-ion M-1=381.09.
Example D-147
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy group)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-146c), by 6-(4-methoxyl group-phenoxy group)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-146b2) preparation.MS-(-)-ion: M-1=381.10.
Example D-148
[(6-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A. (5-hydroxyl-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate
Be similar to example D-100c), by 4-hydroxyl-phthalic acid and glycine ethyl ester hydrochloride preparation. 1H NMR(200MHz,DMSO-d 6)δ11.0(br s,1H),7.74(d,J=7.8Hz,1H),7.17(m,2H),4.35(s,2H),4.13(q,J=7.0Hz,2H),1.20(t,J=7.0Hz,3H)。
B. (5-cyclohexyloxy-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate
Hexalin (3.2g), diethyl azodiformate (6.9g) are added into to (5-hydroxyl-1,3-dioxy-1,3-dihydro-isoindole-2-yl) in-mixture of ethyl acetate (8.0g) in anhydrous tetrahydro furan (160ml) and then add triphenylphosphine (12.6g).At room temperature stir whole night gained mixture concentrated.Resistates is divided between water and ethyl acetate molten.Be extracted with ethyl acetate water layer.Clean and merge organic phase with salt solution, via dried over mgso filtration.Concentrating filtrate also passes through silica gel chromatography (with 5% eluent ethyl acetate in methylene dichloride) purifying to produce title compound (6.2g). 1H NMR(200MHz,CDC1 3)δ7.73(dd,J=8.2,0.8Hz,1H),7.30(br s,1H),7.12(m,1H),4.38(m,3H),4.21(q,J=7.1Hz,2H),2.02(m,2H),1.82-1.25(m,13H)。
C.6-with 7-cyclohexyloxy-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1d) prepare, produce 7-cyclohexyloxy-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-148c1) (MS-(+)-ion M+1=360.16) and 6-cyclohexyloxy-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-148c2) (MS-(+)-ion M+1=360.18).
D.1-bromo-6-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-146a), by 6-cyclohexyloxy-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-148c2) preparation.MS-(+)-ion M+1=422.10,424.10.
E.6-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
10%Pd/C (50% is wet) (460mg) is added in the bromo-6-cyclohexyloxy of the l--4-hydroxyl-mixture of isoquinoline-3-carboxylic acid butyl ester (1.0g) in ethyl acetate (20ml) and then adds ammonium formiate (1.5g).Backflow gained mixture 4h.After cooling, filter reaction mixture concentrated.By silica gel chromatography (the 5%-10% ethyl acetate in methylene dichloride) purifying resistates to produce title compound (640mg).MS-(+)-ion M+1=344.22.
F.[(6-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-146c) prepare.MS-(-)-ion M-1=343.15.
Example D-149
[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A.1-bromo-7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-146a), by 7-cyclohexyloxy-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-148c1), prepared.MS-(+)-ion M+1=422.12,424.12.
B.7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-148e) prepare.MS-(+)-ion M+1=344.22.
C.[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-146c) prepare.MS-(-)-ion M-1=343.17.
Example D-150
[(7-cyclohexyloxy-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A.7-cyclohexyloxy-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-146b) prepare.MS-(+)-ion M+1=358.21.
B.[(7-cyclohexyloxy-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-146c) prepare.MS-(+)-ion M+1=359.15.
Example D-151
[(7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A. (5-hexamethylene sulfenyl-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ethyl acetate
By 5-nitro-isoindole-1,3-diketone (10.0g), hexanaphthene mercaptan (9.1g) and the mixture of salt of wormwood (18.7g) in acetone (260ml) are heated to reflux whole night.After cooling, water (250ml) dilutes this mixture and then with 6N HCl, is acidified to pH=4.The collecting precipitation thing is also dry to produce intermediate 5-hexamethylene sulfenyl-isoindole-1,3-diketone (15.6g) in a vacuum.This intermediate is dissolved in acetone (170mg) and ethyl bromoacetate (10.6g) and salt of wormwood (23.8g) are added so far in mixture.Reflux this mixture whole night.After cooling, filter reaction mixture and use ethyl acetate rinse.Concentrating filtrate also passes through silica gel chromatography (the 10%-50% ethyl acetate in methylene dichloride) purifying to produce title compound (13.1g). 1HNMR(200MHz,CDC1 3)δ7.73(m,2H),7.56(dd,J=7.8,1.6Hz,1H),4.40(s,2H),4.21(q,J=7.0Hz,2H),3.37(m,1H),2.07-1.28(m,13H)。
B.6-with 7-hexamethylene sulfenyl-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-21b) prepare.MS-(+)-ion M+1=376.20.
C.6-with 7-hexamethylene sulfenyl-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Heating in microwave reactor (sealed tube) (180 ℃, 30min) 6-and 7-hexamethylene sulfenyl-Isosorbide-5-Nitrae-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (1.0g) and the mixture of phosphorus oxychloride (491mg) in dry toluene (14ml).After cooling, with saturated sodium bicarbonate, make the reaction mixture quenching.At stirring at room 20min and be extracted with ethyl acetate 2 times.To merge organic layer water, salt solution cleaning, via dried over mgso, filtration concentrated to produce title compound (0.5g).MS-(+)-ion M+1=394.12.
D.6-with 7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-1f) prepare, produce 7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (128mg) (Compound D-151d1) (MS-(+)-ion M+1=360.15) and 6-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (130mg) (Compound D-151d2) (MS-(+)-ion M+1=360.17).
E) [(7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), by 7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-151d1), prepared.MS-(-)-ion M-1=359.11.
Example D-152
[(7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
By 7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-151d1) (64mg) and the mixture of m-chlorine peroxybenzoic acid (111mg) in methylene dichloride (2ml) stirred overnight at room temperature.With methylene dichloride (50ml) dilution, also use successively saturated sodium bicarbonate aqueous solution (2 * 50ml), water and salt solution to clean it.Via dried over mgso organic layer filtration.Concentrating filtrate also passes through silica gel chromatography (with the 3%-15% eluent ethyl acetate in methylene dichloride) purifying to produce title compound (70mg).MS-(+)-ion M+1=392.20.
B.[(7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-146c) prepare.MS-(-)-ion M-1=391.05.
Example D-153
[(4-hydroxyl-1-isobutyl--isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A.4-benzyloxy-1-isobutyl--isoquinoline-3-carboxylic acid butyl ester
The bromo-isoquinoline-3-carboxylic acid butyl ester of the 4-benzyloxy-1-that under agitation refluxes (207mg, 0.5mmol are shown in example D-86a), Pd (PPh 3) 4(58mg, 0.05mmol), 2-methyl-propyl boric acid (78mg, 0.75mmol), K 2cO 3the mixture 48h of (207mg, 1.5mmol) and Isosorbide-5-Nitrae-dioxane (4ml).Concentrate in a vacuum subsequently this mixture.Water (5ml) is added in resistates and extracts this mixture with EtOAc (2 * 20ml).Via MgSO 4dry organic phase evaporation in a vacuum.By flash column chromatography, on silica gel, use hexane: EtOAc=88:12 to carry out the purifying resistates as elutriant, produce the title compound (136mg) that is micro-yellow oil; MS-(+)-ion: M+1=392.3.
B) 4-hydroxyl-1-isobutyl--isoquinoline-3-carboxylic acid butyl ester
At H 2stir the mixture 24h of 4-benzyloxy-1-isobutyl--isoquinoline-3-carboxylic acid butyl ester (125mg, 0.32mmol), Pd/C (50mg, Aldrich, 10 % by weight Pd) and EtOAc (15ml) under-atmosphere at environmental stress and temperature.Then by Celite pad, filter this mixture.Concentrating filtrate and obtain being the title compound (87mg) of micro-yellow oil in a vacuum; MS-(+)-ion M+1=302.2.
C) [(4-hydroxyl-1-isobutyl--isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-isobutyl--isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=303.2.
Example D-154
[(4-hydroxyl-1-pyridine-2-base-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A.4-benzyloxy-1-pyridine-2-base-isoquinoline-3-carboxylic acid butyl ester
In succession by toluene (15mml), the bromo-isoquinoline-3-carboxylic acid butyl ester of 4-benzyloxy-1-(1.035mg, 2.5mmol are shown in example D-86a), Pd (PPh 3) 4(292mg, 0.25mmol) and 2M Na 2cO 3the aqueous solution (2.5ml, 5mmol) is added in EtOH (2.5ml) solution of pyridine-2-ylboronic acid (323mg, 2.5mmol).Then at N 2lower this mixture of the stirring and refluxing 24h of protection.Subsequently, concentrate in a vacuum this mixture.Water (15ml) is added in resistates and extracts this mixture with EtOAc (30ml).Via MgSO 4dry organic phase evaporation in a vacuum.Use CH on silica gel by flash column chromatography 2cl 2: MeOH=98:2 carrys out the purifying resistates as elutriant, produces black oil, and it uses CH on silica gel by flash column chromatography 2cl 2: MeOH=99:1 is further purified as elutriant, and uses CH by preparation TLC subsequently 2cl 2: MeOH=98:2 produces as elutriant (must repeated several times) title compound (19mg) that is yellow oil; MS-(+)-ion M+1=413.2.
B) 4-hydroxyl-1-pyridine-2-base-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-153b), synthetic by 4-benzyloxy-1-pyridine-2-base-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=321.4.
C) [(4-hydroxyl-1-pyridine-2-base-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 4-hydroxyl-1-pyridine-2-base-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=324.1.
Example D-155
[(1-ethyl-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) 4-hydroxyl-7-phenoxy group-1-vinyl-isoquinoline-3-carboxylic acid butyl ester
At N 2the lower bromo-4-hydroxyl of stirring and refluxing 1-of protection-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester (416mg, 1mmol are shown in example D-28a), Pd (PPh 3) 4(118mg, 0.1mmol), 2,4,6-triethylene basic ring three boroxanes-pyridine complex (241mg, 1mmol), K 2cO 3the mixture 3h of (414mg, 3mmol) and Isosorbide-5-Nitrae-dioxane (8ml).Concentrate in a vacuum subsequently this mixture.Water (5ml) is added in resistates and extracts this mixture with EtOAc (20ml).Via MgSO 4dry organic phase evaporation in a vacuum.By flash column chromatography, on silica gel, use hexane: EtOAc=98:2 to carry out the purifying resistates as elutriant, produce the title compound (65mg) that is micro-yellow solid; MS-(+)-ion: M+1=364.1.
B) 1-ethyl-4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-153b), synthetic by 4-hydroxyl-7-phenoxy group-1-vinyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=366.1.
C) [(1-ethyl-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 1-ethyl-4-hydroxyl-7-phenoxy group-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=367.1.
Example D-156
[(1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A.1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Stir at ambient temperature 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (177mg, 0.5mmol; See example D-1f), iodate N, N-dimethylated methylene base ammonium (94mg, 0.5mmol), K 2cO 3(104mg, 0.75mmol) and anhydrous CH 2cl 2(3ml) mixture 2.5 days, then concentrate this mixture in a vacuum.Water (15ml) is added in resistates, by adding the 6N HCl aqueous solution, carrys out this mixture of acidifying and then use Et 2o (3 * 30ml) cleans.Subsequently by adding dense NaHCO 3the aqueous solution neutralizes this mixture and extracts (20ml) with EtOAc.Via MgSO 4dry organic phase also concentrates the title compound (34mg) that is black oil with generation in a vacuum; MS-(+)-ion: M+1=411.1.
B) [(1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-1g), synthetic by 1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=412.0.
Example D-157
[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
A) the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid
Stir Isosorbide-5-Nitrae-dihydroxyl in the 600ml anhydrous acetonitrile-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (example D-1d) compd A under refluxing) (29.0g) and bromine phosphorus oxide (67.5g) 4 hours.After cooling, concentrated reaction mixture also is added into saturated sodium bicarbonate solution and ethyl acetate in resistates and stirs whole night.The throw out the water that are collected in interlayer formation clean to produce title compound (10.2g).MS-(+)-ion M+1=376.0,378.1.
B) the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters
By the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline-3-carboxylic acid (10.0g), salt of wormwood (3.7g) and methyl-sulfate (3.4g), be suspended in 500ml acetone and stirred overnight under refluxing.Concentrated reaction mixture also makes resistates minute molten between 1N hydrochloric acid and ethyl acetate.Via dried over mgso organic layer filtration.Concentrating filtrate is to produce title compound (9.6g).MS-(+)-ion M+1=389.9,391.9.
C) 4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters
The bromo-4-hydroxyl of 1-in microwave reactor (sealed tube) in 140 ℃ of heating Isosorbide-5-Nitrae-dioxanes (4ml)-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters (0.2g), tetrakis triphenylphosphine palladium (60mg), trimethylboroxin (65mg) and salt of wormwood 10min.After cooling, concentrated reaction mixture also divides molten between 1N hydrochloric acid and ethyl acetate.Via dried over mgso organic layer filtration.Concentrating filtrate also separates to produce title compound (47mg) by silica gel chromatography (with 2% eluent ethyl acetate in methylene dichloride).MS-(+)-ion M+1=326.1.
D) [(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid
Be similar to example D-146c) prepare.MS-(+)-ion M+1=369.1.
Example D-158
{ [4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
A.4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester
Be similar to example D-157d), by the chloro-7-of 4-hydroxyl-1-(4-trifluoromethyl-phenoxy group)-isoquinoline-3-carboxylic acid butyl ester (example D-92f), prepared.MS-(+)-ion M+1=420.2.
B) { [4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid
Be similar to example D-146c) prepare.MS-(+)-ion M+1=421.2.

Claims (9)

1. the compound meaned by formula I:
Figure FDA00002247957100011
Wherein:
Q is 0 or 1;
P is 0 or 1;
R abe-COOH or-WR 8; Restricted condition is for working as R aduring for-COOH, p is 0 and works as R afor-WR 8the time p be 1;
W select free oxygen ,-S (O) n-and-NR 9the group of-composition, wherein n is 0,1 or 2; R 9select free hydrogen, alkyl, be substituted alkyl, acyl group, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms; And R 8select free hydrogen, alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms; Perhaps working as W is-NR 9-time, R 8and R 9can couple together and form heterocycle or be substituted heterocyclic radical together with the nitrogen-atoms of its combination, restricted condition is for as W being-S (O) n-and n be 1 or 2 o'clock, R 8be not hydrogen;
R 1the choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Amino; Be substituted amino; Aminoacyl; Aryl; Be substituted aryl; Halogen; Heteroaryl; Be substituted heteroaryl; Heterocycle; Be substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, or as X be-NR 7-time, R 7and R 8can couple together and form heterocycle or be substituted heterocyclic radical together with the nitrogen-atoms of its combination;
R 2and R 3the independent choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Halogen; Hydroxyl; Cyano group;-S (O) n-N (R 6)-R 6, wherein n is 0,1 or 2;-NR 6c (O) NR 6r 6;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, each R 6independently select free hydrogen, alkyl, be substituted alkyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, restricted condition for as X being-SO-or-SO 2-time, R 6be not hydrogen, and R 7the group that selects free hydrogen, alkyl, aryl to form, or R 2, R 3together with side joint, carbon atom thereon forms aryl, the heteroaryl replaced through aryl or is substituted heteroaryl;
R 4and R 5the independent choosing group that freely following each base forms: hydrogen; Halogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, or as X be-NR 7-time, R 7and R 8can couple together and form heterocycle or be substituted heterocyclic radical together with the nitrogen-atoms of its combination;
The group that R selects free hydrogen, deuterium and methyl to form;
R' selects free hydrogen, deuterium, alkyl and is substituted the group that alkyl forms; Perhaps, R and R' and side joint carbon thereon can couple together and form cycloalkyl, is substituted cycloalkyl, heterocycle or is substituted heterocyclic radical;
R " group that selects free hydrogen and alkyl to form, or R " can couple together and forms heterocycle or be substituted heterocyclic radical together with R' and side joint nitrogen thereon;
R ' " select free hydroxyl, alkoxyl group, be substituted alkoxyl group, acyloxy, cycloalkyloxy, be substituted cycloalkyloxy, aryloxy, be substituted aryloxy, heteroaryloxy, be substituted heteroaryloxy, aryl ,-S (O) n-R 10the group formed, wherein R 10select free alkyl, be substituted alkyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl and be substituted the group that heteroaryl forms, and n is 0,1 or 2;
And pharmaceutically acceptable salt and ester;
Restricted condition is as R, R' and R, and " be hydrogen, q is 0, and R afor-COOH (p is 0) or-WR 8(p is 1), W is oxygen and R 8during for hydrogen, following at least one situation occurs:
1) R 1for fluorine; Bromine; Iodine; Alkyl; Be substituted alkyl; Alkoxyl group; Aminoacyl; Be substituted alkoxyl group; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Heterocycle; Be substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl; Perhaps
2) R 2for being substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Fluorine; Bromine; Iodine; Cyano group;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 2when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; With
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise benzyl or through selecting freedom (C 1-C 5) alkyl and (C 1-C 5) benzyl that replaces of the substituting group of the group that forms of alkoxyl group or the fluoroalkyl substituting group that does not comprise following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
3) R 3for being substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Bromine; Iodine;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 3when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; With
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise benzyl or through selecting freedom (C 1-C 5) alkyl and (C 1-C 5) benzyl that replaces of the substituting group of the group that forms of alkoxyl group or the fluoroalkyl substituting group that does not comprise following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
4) R 4for iodine; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 4when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; With
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise the fluoroalkyl substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
5) R 5for iodine; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 5when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; With
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise the fluoroalkyl substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1);
And further there is following restricted condition:
Work as R 1, R 3, R 4and R 5during for hydrogen, R 2it is not bromine.
2. compound according to claim 1, wherein said compound is meaned by formula ID:
Figure FDA00002247957100041
R wherein 1, R 2, R 3, R 4, R 5, R ", R' " and q defined as claim 1; And pharmaceutically acceptable salt and ester.
3. compound according to claim 1, wherein said compound is meaned by formula IID:
Wherein:
Q is 0 or 1;
R " is selected from hydrogen and alkyl;
R 1the choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Aryl; Be substituted aryl; Halogen; Heteroaryl; Be substituted heteroaryl; Heterocycle; Be substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl;
R 2and R 3the independent choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Halogen; Hydroxyl; Cyano group;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6independently select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7hydrogen, alkyl or aryl;
R 4and R 5the independent choosing group that freely following each base forms: hydrogen; Halogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl; Or
Its pharmaceutically acceptable salt.
4. a compound that is selected from the group formed by following material:
{ [4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(3-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(the fluoro-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(the fluoro-phenoxy group of 2-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(2-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-(4-acetylaminohydroxyphenylarsonic acid phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(4-methanesulfonamido-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(4-hydroxyl-1-phenyl amino-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(1-chloro-4-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the chloro-4-oxyethyl group-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-oxyethyl group-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-oxyethyl group-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the chloro-4-phenyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methoxy methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-dimethylamino formyl radical-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-benzyloxy-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-oxyethyl group-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-dimethylamino formyl radical-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the p-tolyl-isoquinoline 99.9 of 4-hydroxyl-1--3-carbonyl)-amino]-acetic acid;
{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [the chloro-7-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [the chloro-6-of 1-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(7-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(6-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(6-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(6-amino-4-hydroxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-7-(4-methoxyl group-phenylsulfonamido)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(the p-tolyl sulfenyl-isoquinoline 99.9 of 4-hydroxyl-1--3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-1-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(3-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(2-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-1-(naphthalene-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(1-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-7-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(1-chloro-4-hydroxyl-6,7-bis-phenoxy groups-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-6,7-bis-phenoxy groups-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
(4-hydroxyl-7-[4-(toluene-4-sulfuryl amino)-phenoxy group]-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid;
{ [4-hydroxyl-7-(4-nitro-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(4-sulfydryl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-sulfydryl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [7-(4-phenylsulfonamido-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-methanesulfonamido-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-trifluoromethoxy-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(4-trifluoromethoxy-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
2-(S)-{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-{[7-(the fluoro-phenoxy group of 3,4-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(R)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(R)-[(4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(4-hydroxyl-1-methoxy methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(4-sulfydryl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-{[1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
(R)-2-{[1-(the chloro-phenyl sulfenyl of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--6-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [7-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [the chloro-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [the bromo-7-of 1-(2,6-dimethyl-phenoxy group)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(the bromo-7-chloro-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(the bromo-6-chloro-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--6-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 1,7-bis--3-carbonyl)-amino]-acetic acid;
[(the bromo-1-chloro-4-hydroxyl-isoquinoline 99.9 of 7--3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 6--3-carbonyl)-amino]-acetic acid;
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of the bromo-7-of 1--3-carbonyl)-amino]-acetic acid;
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of 7--3-carbonyl)-amino]-acetic acid;
[(the fluoro-4-hydroxyl-isoquinoline 99.9 of the chloro-7-of 1--3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-benzo [g] isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl-isoquinoline 99.9 of 1--3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-ethyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-1-(4-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(the iodo-isoquinoline 99.9 of 1-chloro-4-hydroxyl-7--3-carbonyl)-amino]-acetic acid;
[(the iodo-isoquinoline 99.9 of 1-chloro-4-hydroxyl-6--3-carbonyl)-amino]-acetic acid;
[(the iodo-isoquinoline 99.9 of 4-hydroxyl-7--3-carbonyl)-amino]-acetic acid;
[(the bromo-4-hydroxyl of 1--7-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-7-butoxy of 1--4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(the bromo-6-butoxy of 1--4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid;
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid;
[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid;
[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetic acid;
[carboxymethyl-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[carboxymethyl-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-acetylaminohydroxyphenylarsonic acid ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid;
2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(1H-imidazol-4 yl)-propionic acid (three fluoro-acetates);
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(1H-imidazol-4 yl)-propionic acid (three fluoro-acetates);
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid;
(R)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(S)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(R)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(S)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(R)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(S)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate;
(S)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate;
(S)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
1-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropanecarboxylic acid;
1-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropanecarboxylic acid;
Two deuteriums-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
(R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
{ [7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
(7-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid;
(6-[4-(the fluoro-phenoxy group of 4-)-phenoxy group]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetic acid;
{ [7-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the fluoro-phenoxy group of the chloro-4-of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
(S)-2-{[7-(the fluoro-5-methoxyl group-phenoxy group of 3-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(7-cyclohexyl oxygen base-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-{ [7-(the fluoro-phenoxy group of 4-)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(4-hydroxyl-1-methyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
{ [7-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [6-(the chloro-phenoxy group of 4-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [7-(the fluoro-phenoxy group of 3,5-bis-)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy group)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy group)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid;
[(6-cyclohexyl oxygen base-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-cyclohexyl oxygen base-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-cyclohexyl oxygen base-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-cyclohexyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-isobutyl--isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-pyridine-2-base-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-ethyl-4-hydroxyl-7-phenoxy group-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetic acid;
{ [4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy group)-isoquinoline 99.9-3-carbonyl]-amino }-acetic acid; With its pharmaceutically acceptable salt and ester.
5. compound according to claim 1, wherein said compound is meaned by formula 3:
Figure FDA00002247957100141
R wherein 1, R 2, R 3, R 4, R 5, R, R', R ", R' " and R aas claim 1 is defined; And pharmaceutically acceptable salt and ester.
6. the preparation method of the compound of formula 3,
Figure FDA00002247957100142
Described method comprises:
Compound by formula 1
Figure FDA00002247957100143
Under conventional coupling condition with the compound chemical combination of formula 2
Figure FDA00002247957100144
Wherein Pg is protecting group, and
R abe-COOH:
R 1the choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Amino; Be substituted amino; Aminoacyl; Aryl; Be substituted aryl; Halogen; Heteroaryl; Be substituted heteroaryl; Heterocycle; Be substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, or as X be-NR 7-time, R 7and R 8can couple together and form heterocycle or be substituted heterocyclic radical together with the nitrogen-atoms of its combination;
R 2and R 3the independent choosing group that freely following each base forms: hydrogen; Alkyl; Through substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Halogen; Hydroxyl; Cyano group;-S (O) n-N (R 6)-R 6, wherein n is 0,1 or 2;-NR 6c (O) NR 6r 6;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, each R 6independently select free hydrogen, alkyl, be substituted alkyl, aryl, be substituted aryl, cycloalkyl, be substituted cycloalkyl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, restricted condition for as X being-SO-or-SO 2-time, R 6be not hydrogen, and R 7the group that selects free hydrogen, alkyl, aryl to form, or R 2, R 3together with side joint, carbon atom thereon forms aryl, the heteroaryl replaced through aryl or is substituted heteroaryl;
R 4and R 5the independent choosing group that freely following each base forms: hydrogen; Halogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, or as X be-NR 7-time, R 7and R 8can couple together and form heterocycle or be substituted heterocyclic radical together with the nitrogen-atoms of its combination;
The group that R selects free hydrogen, deuterium and methyl to form;
R' selects free hydrogen, deuterium, alkyl and is substituted the group that alkyl forms; Perhaps, R and R' and side joint carbon thereon can couple together and form cycloalkyl, is substituted cycloalkyl, heterocycle or is substituted heterocyclic radical;
R " group that selects free hydrogen and alkyl to form, or R " can couple together and forms heterocycle or be substituted heterocyclic radical together with R' and side joint nitrogen thereon;
R ' " select free hydroxyl, alkoxyl group, be substituted alkoxyl group, acyloxy, cycloalkyloxy, be substituted cycloalkyloxy, aryloxy, be substituted aryloxy, heteroaryloxy, be substituted heteroaryloxy, aryl ,-S (O) n-R 10the group formed, wherein R 10select free alkyl, be substituted alkyl, cycloalkyl, be substituted cycloalkyl, aryl, be substituted aryl, heteroaryl and be substituted the group that heteroaryl forms, and n is 0,1 or 2;
And pharmaceutically acceptable salt and ester;
Restricted condition is as R, R' and R, and " be hydrogen, q is 0, and R afor-COOH (p is 0) or-WR 8(p is 1), W is oxygen and R 8during for hydrogen, following at least one situation occurs:
1) R 1for fluorine; Bromine; Iodine; Alkyl; Be substituted alkyl; Alkoxyl group; Aminoacyl; Be substituted alkoxyl group; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Heterocycle; Be substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl; Perhaps
2) R 2for being substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Fluorine; Bromine; Iodine; Cyano group;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 2when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; With
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise benzyl or through selecting freedom (C 1-C 5) alkyl and (C 1-C 5) benzyl that replaces of the substituting group of the group that forms of alkoxyl group or the fluoroalkyl substituting group that does not comprise following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
3) R 3for being substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Bromine; Iodine;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 3when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; With
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise benzyl or through selecting freedom (C 1-C 5) alkyl and (C 1-C 5) benzyl that replaces of the substituting group of the group that forms of alkoxyl group or the fluoroalkyl substituting group that does not comprise following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
4) R 4for iodine; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 4when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; With
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise the fluoroalkyl substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1); Or
5) R 5for iodine; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl;
-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl, restricted condition is:
A) work as R 5when being substituted alkyl, described substituting group does not comprise trifluoromethyl;
B)-XR 6it is not alkoxyl group; With
C) as-XR 6when being substituted alkoxyl group, described substituting group does not comprise the fluoroalkyl substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; The integer that f is 1 to 5; And g is 1 integer to (2f+1);
And further there is following restricted condition:
Work as R 1, R 3, R 4and R 5during for hydrogen, R 2it is not bromine.
7. method according to claim 6 further comprises:
The step of the compound of recovery type 3.
8. method according to claim 6, wherein R and R' are hydrogen.
9. method according to claim 8, wherein
R 1the choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Aryl; Be substituted aryl; Halogen; Heteroaryl; Be substituted heteroaryl; Heterocycle; Be substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl;
R 2and R 3the independent choosing group that freely following each base forms: hydrogen; Alkyl; Be substituted alkyl; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; Halogen; Hydroxyl; Cyano group;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6independently select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7hydrogen, alkyl or aryl;
R 4and R 5the independent choosing group that freely following each base forms: hydrogen; Halogen; Alkyl; Be substituted alkyl; Alkoxyl group; Be substituted alkoxyl group; Aryl; Be substituted aryl; Heteroaryl; Be substituted heteroaryl; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6select free alkyl, be substituted alkyl, aryl, be substituted aryl, heteroaryl, be substituted heteroaryl, heterocycle and be substituted the group that heterocycle forms, and R 7for hydrogen, alkyl or aryl.
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